cholecystokinin and anxiety


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(Updated 3/4/04)

Fink H, Rex A, Voits M, Voigt JP.
Major biological actions of CCK--a critical evaluation of research findings.
Exp Brain Res 1998 Nov;123(1-2):77-83
"Cholecystokinin (CCK) is one of the first discovered gastrointestinal hormones and one of the most abundant neuropeptides in the brain. Two types of CCK receptors have been identified: (1) CCK-A receptors are mainly located in the periphery, but are also found in some areas of the CNS; and (2) CCK-B receptors are widely distributed in the brain. Major biological actions of CCK are the reduction of food intake and the induction of anxiety-related behavior. Inhibition of feeding is mainly mediated by the A-type receptors, whereas anxiety-like behavior is induced by stimulating B-type receptors. This paper presents new findings on the effects of the biologically active CCK agonists, CCK-8S, CCK-4, and A71378. The results reviewed suggest that the hypophagic effects of CCK are strongly dependent on the experimental design, sex, and age of the rats. For example, food intake measured during the night or after food deprivation is reduced by CCK-8S in young adult and aged rats, whereas, under fixed feeding conditions, CCK-8S does not inhibit food intake in young adult rats. The sensitivity to the hypophagic CCK effect increases with age in male and female rats; however, female rats are less sensitive to the CCK action. Further, using a nongenetic and non-stressful model of obesity due to unspecific postnatal overfeeding, the satiating effect of moderate CCK-8S doses is weaker in obese than in normal rats. Again, the hypophagic effect is more pronounced in male than in female obese and normal rats. Considering that aversive reactions in rats are markedly influenced by strain and breeding-line variations, research results in this area are critically reviewed. It is shown that anxiety-like symptoms can only be induced by a selectively acting CCK-B agonist, whereas mixed CCK-A and -B agonists and selective CCK-A agonists fail to change behavior in anxiety tests. CCK-4 induces stable and reproducible anxiogenic-like behavior only in certain rat strains. Moreover, CCK-4 effects can be demonstrated in the conflict test, in the ultrasonic vocalization test in rat pups, on the elevated plus maze, and in the black and white box, but not in the social interaction test. CCK has also been reported to modulate memory processes. On the one hand, CCK-8S and CCK-4 enhanced habituation to the novelty of a hole board. On the other hand, repeated administration of CCK-8S did not improve maze performance in aged rats. The literature on the behavioral pharmacology of CCK is rife with inconsistency and contradiction. The major biological actions of CCK depend on the receptor selectivity of the CCK fragments used and on organismic and procedural variables. All these variables potentially influence behavioral responses in rats. Therefore, in CCK research more attention should be paid to the importance of these methodological factors." [Abstract]

Wank SA.
Cholecystokinin receptors.
Am J Physiol 1995 Nov;269(5 Pt 1):G628-46
"The cholecystokinin (CCK) and gastrin families of peptides act as hormones and neuropeptides on central and peripheral CCK receptors to mediate secretion and motility in the gastrointestinal (GI) tract in the physiological response to a normal meal. CCK and its receptors are also widely distributed in the central nervous system (CNS) and contribute to the regulation of satiety, anxiety, analgesia, and dopamine-mediated behavior. Although the wide distribution, myriad number of functions, and reported pharmacological heterogeneity of CCK receptors would suggest a large number of receptor subtypes, the application of modern molecular biological techniques has identified two CCK receptors, CCK-A receptor (CCK-AR) and CCK-B receptor (CCK-BR), that mediate the actions of CCK and gastrin; gastrin receptors have been found to be identical to CCK-BR. CCK-AR, found predominantly in the GI system and select areas of the CNS, have high affinity for CCK and the nonpeptide antagonist L-364,718, whereas CCK-BR, found predominantly in the CNS and select areas of the GI system, have high affinity for CCK and gastrin and the nonpeptide antagonist L-365,260. Both CCK-AR and CCK-BR are highly conserved between species, although there is some tissue-specific variation in expression. Recombinant receptor expression faithfully reproduces the native receptor pharmacology and signal transduction pathways, allowing direct comparisons of receptor function between species as well as serving as a convenient source of receptor. Our present knowledge of the chromosomal localization, receptor gene structure, and primary sequence will allow further studies in disease association, receptor regulation, and structure-function analysis." [Abstract]

Wunderlich GR, Raymond R, DeSousa NJ, Nobrega JN, Vaccarino FJ.
Decreased CCK(B) receptor binding in rat amygdala in animals demonstrating greater anxiety-like behavior.
Psychopharmacology (Berl) 2002 Nov;164(2):193-9
"RATIONALE. The potentiation of the acoustic startle response (ASR) by stimuli associated with aversive events is mediated via the amygdala and is used as an index of "anxiety" and "fear". In laboratory animals, cholecystokinin(B) (CCK(B)) agonists increase anxiety and fear and activation of amygdala CCK(B) receptors potentiates ASR. Additionally, antagonism of CCK(B) receptors attenuates fear-potentiated ASR. OBJECTIVES. To investigate the putative role of CCK(B) receptors in individual differences in fear and anxiety, we examined individual differences in amygdala CCK(B) receptor binding for animals demonstrating low versus high baseline and fear-potentiated ASR. Additionally, we examined individual differences in CCK(B) binding for animals demonstrating low versus high anxiety-like behavior on the elevated plus-maze (EPM). METHODS. Male Wistar rats were tested in the ASR, fear-potentiated ASR, and EPM paradigms. Following testing, brain slices were mounted and incubated with 50 pM (125)I-CCK8 (non-sulfated), a selective CCK(B) receptor ligand, in the presence or absence of 1 micro M non-radioactively labeled CCK and then exposed on tritium-sensitive film for 2-3 days. RESULTS. Animals with high fear-potentiated ASR showed decreased CCK(B) receptor binding in both the basolateral and central amygdaloid nuclei. Animals with high anxiety-like responses on the EPM showed decreased CCK(B) binding in the basolateral, but not central, amygdala. There were no differences in amygdala CCK(B) binding in animals demonstrating low versus high baseline ASR. None of the groups showed differences in CCK(B) receptor binding in the nucleus accumbens. CONCLUSIONS. These results show that there is a down-regulation of amygdala CCK(B) receptor binding in animals demonstrating greater anxiety-like responding in the fear-potentiated ASR and EPM models of anxiety, possibly as a compensation for increased CCK activity." [Abstract]

Becker, Chrystel, Thiebot, Marie-Helene, Touitou, Yvan, Hamon, Michel, Cesselin, Francois, Benoliel, Jean-Jacques
Enhanced Cortical Extracellular Levels of Cholecystokinin-Like Material in a Model of Anticipation of Social Defeat in the Rat
J. Neurosci. 2001 21: 262-269
"The involvement of cholecystokinin (CCK) in the mechanisms of stress and/or anxiety was assessed by in vivo microdialysis in rats subjected to a social stress paradigm. During the initial 30 min period of each conditioning session, a male Sprague Dawley rat (intruder) was placed in a protective cage inside the cage of a male Tryon Maze Dull rat (resident), allowing unrestricted visual, olfactory, and auditory contacts but precluding close physical contact between them. During the following 15 min period, both the protective cage and the resident were removed (nondefeated intruders) or only the protective cage was removed allowing the resident to attack the intruder (defeated rats). This procedure was repeated once daily for 4 d. On the fifth day, a guide cannula was implanted into the prefrontal cortex of intruders. During a single 30 min test session, performed 4 d later, intruders were subjected to only the 30 min protected confrontation to the resident. Anxiety-like behavior (immobility, ultrasonic vocalizations, and defensive postures), associated with an increase (approximately +100% above baseline) in cortical outflow of CCK-like material (CCKLM), were observed in defeated intruders. Pretreatment with diazepam (5 mg/kg, i.p.), but not buspirone (0.5-2 mg/kg, i.p.), prevented both the anxiety-related behavior and CCKLM overflow. The selective CCK-B receptor antagonist CI-988 (2 mg/kg, i.p.) reduced the anxiety-like behavior without affecting the increase in CCKLM outflow. These data indicate that anticipation of social defeat induces a marked activation of cortical CCKergic neurons associated with anxiety-related behaviors in rats." [Full Text]

Radu D, Ahlin A, Svanborg P, Lindefors N.
Anxiogenic effects of the CCK(B) agonist pentagastrin in humans and dose-dependent increase in plasma C-peptide levels.
Psychopharmacology (Berl) 2002 Jun;161(4):396-403
"RATIONALE: Cholecystokinin type B (CCK(B)) receptor agonists such as pentagastrin or CCK-4 have panic-like anxiogenic effects in humans. It has also been shown that CCK-4 can stimulate insulin release and thus C-peptide release from pancreatic islet cells. Combined, these mechanisms may provide a basis for a bioassay.OBJECTIVES: Our aim was to study if a pentagastrin bolus injection evokes insulin release (as measured by C-peptide) and if the levels of C-peptide correlate to the anxiogenic effect of pentagastrin.METHODS: Pentagastrin was given in bolus IV injections to healthy volunteers at increasing doses (0.003, 0.012, 0.05 and 0.2 microg/kg).RESULTS: A significant increase in the plasma level of C-peptide was observed 2-4 min after the highest dose of pentagastrin. This increase was accompanied by a transient panic-like anxiety within 2 min following pentagastrin, measured using a state anxiety scale. Also, 0.05 microg/kg pentagastrin gave a minor but significant subjective discomfort at the same time interval. The basal plasma level of C-peptide preceding the pentagastrin injection showed a positive correlation to the intensity of the subsequent pentagastrin-induced panic-like anxiety as rated on the state anxiety scale. In addition, basal plasma levels of cortisol were positively correlated to the subsequent pentagastrin-induced increase in plasma C-peptide levels.CONCLUSIONS: Our results imply a possible relationship between insulin/C-peptide release and sensitivity to psychotropic activation by CCK(B) receptor stimulation. Furthermore, we postulate that both basal and pentagastrin-induced plasma levels of C-peptide may possess characteristic phenotype properties for anxiety related traits." [Abstract]

Radu D, Ahlin A, Svanborg P, Lindefors N.
Pentagastrin test for anxiety--psychophysiology and personality.
Psychopharmacology (Berl). 2003 Mar;166(2):139-45. Epub 2003 Jan 16.
"RATIONALE: CCK(B) receptor agonists such as pentagastrin or CCK(4) have anxiogenic panic-like effects in humans. Our previous findings are in agreement with a relationship between C-peptide plasma levels (as a measure of insulin release) and sensitivity to psychotropic activation by CCK(B) receptor stimulation. OBJECTIVES: Our present aim was to study the transient humoral, physiological and psychotropic effects of pentagastrin bolus injection and whether personality might affect the outcome. METHODS: Pentagastrin was given in bolus i.v. injections to healthy volunteers at increasing doses (0.003, 0.012, 0.05 and 0.2 microg/kg). Physiological parameters were recorded before and during each pentagastrin challenge and humoral variables described previously were included in the analyzes. Subjects rated the discomfort following pentagastrin administration on the state anxiety and discomfort scale (SADS). The Karolinska scale of personality (KSP), anxiety sensitivity index (ASI) and Hamilton anxiety scale (HAS) were used to characterize the subjects before the test. RESULTS: Galvanic skin response (GSR) and heart rate (HR) were significantly increased within 1 min following 0.2 microg/kg pentagastrin, the GSR increase correlating negatively to the C-peptide increase and positively to ratings on SADS. Even the lower dose (0.05 microg/kg pentagastrin) induced a significant increase in GSR. ASI measures correlated weakly to the increase in ratings on SADS following 0.05 microg/kg and 0.2 microg/kg pentagastrin. CONCLUSIONS: We found correlations between psychophysiology, humoral response and subjective ratings following pentagastrin administration. CCK(B) receptor stimulation might reveal phenotype properties predictive of anxiety-related traits, measurable through serum levels of C-peptide. Furthermore, our results support the predictive value of ASI for fearfulness." [Abstract]

Kim H, Whang WW, Kim HT, Pyun KH, Cho SY, Hahm DH, Lee HJ, Shim I.
Expression of neuropeptide Y and cholecystokinin in the rat brain by chronic mild stress.
Brain Res. 2003 Sep 5;983(1-2):201-8.
"Neuropeptide Y (NPY) and cholecystokinin (CCK) are known to play important roles in the response to stress and the control of anxiety. In order to investigate the role of NPY and CCK in chronic mild stress (CMS), an animal model of depression, we examined the effects of CMS on sucrose intake as a measure of anhedonia, and expression of NPY and CCK in the rat brain utilizing immunohistochemistry. Sprague-Dawley rats were exposed to a variety of chronic unpredictable mild stressors for 8 weeks. CMS rats significantly reduced the consumption of sucrose intake and gained body weight more slowly, compared to control rats. CMS dramatically produced a decrease in NPY expression in several diencephalic regions including the parvocellular subregion of the paraventricular hypothalamic nucleus (PVN), the periventricular hypothalamic nucleus (PE), the paraventricular thalamic nucleus (PV) and the arcuate nucleus (ACN). In contrast, CCK-like immunoreactivity throughout these areas was substantially increased in chronic mild stressed rats. These results clearly demonstrated that exposure of chronic mild stress upregulated CCK synthesis and downregulated NPY synthesis within the hypothalamus. The present results demonstrated that there was an inverse relationship between NPY and CCK in mediating stress response in an animal model of depression. These findings suggest that CCK and NPY systems may play important roles in expressing the symptopathology of the chronic stress responses such as depression, abnormality of food intake or anxiety-related disorders." [Abstract]

Tsutsumi T, Akiyoshi J, Hikichi T, Kiyota A, Kohno Y, Katsuragi S, Yamamoto Y, Isogawa K, Nagayama H.
Suppression of conditioned fear by administration of CCKB receptor antisense oligodeoxynucleotide into the lateral ventricle.
Pharmacopsychiatry 2001 Nov;34(6):232-7
"We investigated the role of CCK in the development of anxiety by determining whether CCKB receptor antisense suppressed intracellular Ca(2+) concentration in vitro or suppressed conditioned fear stress in vivo. First, for the in vitro studies, we used rat pituitary tumor GH3 cells since these cells have CCKB receptors. GH3 cells were stimulated by 10 microM CCK-4; intracellular Ca(2+) concentration was measured. The CCKB receptor antisense at 1 or 10 microM reduced the subsequent response to 10 microM CCK-4 in a time-dependent manner. Second, for the in vivo studies, the CCKB receptor antisense, sense, random sense, or saline was infused at a constant rate for 6 days into rat lateral ventricles via mini-osmotic pumps. Individual rats were then subjected to 30 min of inescapable electric footshock in a chamber with a grid floor. Twenty-four hours later, the rat was again placed in the chamber and observed for 5 min without shocks. This study showed that CCKB receptor antisense significantly suppressed intracellular Ca(2+) concentration in GH3 cells and significantly reduced freezing behavior in rats, indicating that the CCKB receptor plays an important role in anxiety." [Abstract]

Izumi T.
[Behavioral and neurochemical study on the role of the brain cholecystokinin system in anxiety]
Hokkaido Igaku Zasshi 1998 Sep;73(5):463-73
"In order to elucidate the involvement of cholecystokinin (CCK) in the regulation of anxiety, the author examined the effects of the selective non-peptide CCKB receptor antagonist LY288513 on freezing behavior induced by conditioned fear stress, an animal model of anxiety. Rats were individually subjected to 5 min of inescapable electric footshock in a shock chamber. Twenty-four hours after the footshock, the rats were again placed in the shock chamber and observed for 5 min without shocks: this procedure is termed conditioned fear stress. Subcutaneous administration of LY288513 30 min before footshock (0.3 mg/kg) and 30 min before conditioned fear stress (0.03-0.3 mg/kg) reduced conditioned freezing. This indicates that LY288513 blocked both the acquisition and expression of conditioned fear. The relatively selective non-peptide CCKA receptor antagonist, lorglumide, blocked the expression of conditioned fear, but only at a high dose (1.0 mg/kg). The peripheral non-peptide CCKA/B receptor antagonist, loxiglumide, failed to do so. Subcutaneous administration of LY288513 (3 mg/kg) enhanced the conditioned fear-induced in 3, 4-dihydroxy-phenylacetic acid (DOPAC) contents in the medial prefrontal cortex, which was assayed by high performance liquid chromatography with electrochemical detection. Thirty min of inescapable electric footshock decreased CCK8S contents in the amygdala, which was assayed by radioimmunoassay. These results suggest that the brain CCKB receptors are involved in the regulation of anxiety, and that the anxiolytic effects of CCKB receptor antagonists are mediated by increasing dopamine activity in the medial prefrontal cortex. Furthermore, it is possible that the CCK neurons in the amygdala are also associated with anxiety." [Abstract]

Hansen TV, Nielsen FC.
Regulation of neuronal cholecystokinin gene transcription.
Scand J Clin Lab Invest Suppl 2001;(234):61-7
"Cholecystokinin (CCK) is a neuroendocrine peptide expressed in I-cells of the small intestine and in central and peripheral neurons. Whereas intestinal CCK is involved in the release of pancreatic enzymes and the contraction of the gallbladder, cerebral CCK is implicated in a variety of functions, such as feeding behaviour, anxiety and memory. The expression of CCK is developmentally regulated. Brain CCK mRNA levels are low before birth, but increase markedly shortly after birth and reach adult like patterns of expression three weeks after birth during the final maturation of the central nervous system. In the adult, several substances induce neuronal CCK mRNA expression via activation of transcription factors binding to regulatory elements in the CCK promoter. Recent studies have examined the signaling pathways, transcription factors and regulatory elements involved in cAMP, fibroblast growth factor-2, and calcium-induced CCK gene transcription in neuronal cells. The review describes the signaling pathways and transcription factors involved in neuronal CCK gene transcription." [Abstract]

Bradwejn J, Koszycki D.
Cholecystokinin and panic disorder: past and future clinical research strategies.
Scand J Clin Lab Invest Suppl 2001;(234):19-27
"The involvement of cholecystokinin (CCK) in human anxiety is well documented. Exogenous administration of CCK-2 receptor agonists, such as cholecystokinin-tetrapeptide and pentagastrin, provoke panic attacks in man. Patients with panic disorder (PD) are hypersensitive to CCK-2 receptor stimulation compared to healthy volunteers and patients with other anxiety disorders, and they differ from healthy subjects in CCK metabolism and genetic characteristics of the CCK-2 receptor system. This article reviews the corpus of work supporting the role of CCK in anxiety and suggests three research approaches which can further enhance our understanding of the CCK-2 system in PD. These approaches include: i) searching for a specific anomaly of the CCK-2 receptor system, ii) establishing a relationship between CCK-2 receptor polymorphism and vulnerability to pharmacologically-induced or spontaneous panic attacks, and iii) evaluating the therapeutic efficacy of CCK-2 receptor antagonists which possess adequate pharmacokinetic properties." [Abstract]

Lodge DJ, Lawrence AJ.
Comparative analysis of the central CCK system in Fawn Hooded and Wistar Kyoto rats: extended localisation of CCK-A receptors throughout the rat brain using a novel radioligand.
Regul Pept 2001 Jun 15;99(2-3):191-201
"The neuropeptide cholecystokinin has been implicated in the actions of a number of central processes including anxiety and reward. For this reason, the aim of the present study was to compare the density of CCK-A and -B receptors and the mRNA encoding preproCCK throughout the brains of an alcohol-preferring (Fawn Hooded) rat strain with that of a non-alcohol-preferring (Wistar Kyoto) strain of rat. Our study revealed significant differences with regard to the central CCK system of the FH compared to the WKY rat, including differences in CCK-A receptor binding throughout the dorsal medulla, and altered CCK-B binding density throughout the cerebral cortex and reticular nucleus of the thalamus. The most striking result, given the altered behavioural phenotype of the FH rat, was the 33% lower density of CCKmRNA measured throughout the ventral tegmental area of the FH rat when compared to the WKY. This study also reports on a protocol to utilise a novel radioligand, [125I]-D-Tyr-Gly-A-71378, for autoradiographic detection of CCK-A receptors throughout the rat brain. As previously reported, CCK-A receptors were located throughout the area postrema, interpeduncular nucleus and nucleus tractus solitarii; however, binding to CCK-A receptors was also visualised throughout the medial pre-optic area, the arcuate nucleus and the circumventricular regions of the ventral hypothalamus, regions known to contain CCK-A receptors but which were previously undetectable using autoradiography in rat brain." [Abstract]

Binkley K, King N, Poonai N, Seeman P, Ulpian C, Kennedy J.
Idiopathic environmental intolerance: increased prevalence of panic disorder-associated cholecystokinin B receptor allele 7.
J Allergy Clin Immunol 2001 May;107(5):887-90
"BACKGROUND: A growing body of evidence suggests that idiopathic environmental intolerance (IEI) is a psychophysiologic disorder with prominent features of anxiety/panic and somatization, although proponents of a toxicogenic explanation claim, despite a lack of convincing evidence, that symptoms arise from exposure to otherwise nonnoxious environmental agents. Patient behaviour is characterized by strenuous avoidance of perceived triggers to the point of severe impairment of normal social and vocational functioning. IEI proponents claim that previous studies showing a high prevalence of psychopathology in patients with IEI and studies showing panic responses to known panicogenic challenges merely reflect the anxiety-producing result of living with IEI. OBJECTIVE: We explored whether IEI and panic disorder, personality traits, or both shared an underlying neurogenetic basis that would predate the anxiety of IEI symptomatology. The DNA of patients with IEI was examined for the presence of known panic disorder-associated cholecystokinin B (CCK-B) receptor alleles and for personality trait-associated dopamine D4 receptor polymorphisms. METHODS: Eleven patients with typical IEI symptoms were recruited and were individually matched to normal control subjects from an existing bank for age, sex, and ethnic background. Genomic DNA was extracted from peripheral blood samples. CCK-B and dopamine D4 receptor polymorphisms were examined by using standard PCR-based techniques. RESULTS: There was a significantly higher prevalence of the panic disorder-associated CCK-B receptor allele 7 in subjects with IEI (9/22 [40.9%]) compared with control subjects (2/22 [9.1%], P =.037). There was no difference in personality trait-associated polymorphisms of the gene encoding dopamine D4 receptor between patients and control subjects. CONCLUSIONS: These findings provide preliminary evidence that IEI and panic disorder share a common neurogenetic basis, which would predate the anxiety-producing effects of IEI symptoms. Further studies with larger samples are warranted, but these results support previous studies that suggest that panic disorder may account for much of the symptomatology in at least some cases of IEI and provide a basis for rational treatment strategies." [Abstract]

Gustafsson H, Stiller CO, Brodin E.
Peripheral axotomy increases cholecystokinin release in the rat anterior cingulate cortex.
Neuroreport 2000 Oct 20;11(15):3345-8
"The anterior cingulate cortex (ACC) is a limbic region with a high density of cholecystokinin (CCK) immunoreactivity, that has been suggested to be of importance for the affective and emotional component of pain. In the present microdialysis study, performed in the awake rat, we demonstrate a bilateral 4- to 6-fold increase of the potassium-induced release of CCK-like immunoreactivity (CCK-LI) in the ACC 2-3 weeks after a unilateral transection of the sciatic nerve (axotomy), an animal model of phantom limb or deafferentiation pain. Considering the implication of CCK in pain modulation and anxiety, we suggest that an altered activity of CCK containing neurons in the ACC may be of importance for the affective component of certain pain conditions." [Abstract]

Hansen TV, Rehfeld JF, Nielsen FC.
Function of the C-36 to T polymorphism in the human cholecystokinin gene promoter.
Mol Psychiatry 2000 Jul;5(4):443-7
"Cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain, and in man significant quantities are expressed in all regions of the brain.1,2 Therefore, CCK has been implicated in a variety of CNS functions-such as feeding behavior, anxiety, analgesia and memory functions as well as psychiatric disease like panic disorder and schizophrenia (for review, see2,3). Recently, a number of studies have indicated that a C-36 to T transition in the CCK gene promoter Sp1 element4 (Figure 1) is associated with alcoholism and withdrawal symptoms as well as panic disorder.5-7 Moreover, it has been proposed that the polymorphism plays a direct role in the pathogenesis of the disorders by decreasing the expression and synthesis of CCK peptides. The significance of these findings is still unclear and other studies have failed to demonstrate linkage between the polymorphism and alcoholism.8 In this study we examined the function of the C-36 to T transition in transcription of the human CCK gene. We demonstrate that substitution of the C-36 residue causes a slight reduction of Sp1 and Sp3 binding, but this has no effect on transcription in vivo. Moreover, no difference in the response to physiological stimuli was observed. Taken together the results show that the C to T polymorphism does not play a direct role in the pathogenesis of either alcoholism or panic disorder and that a putative association to these disorders is likely to be the result of co-segregation with a linked mutation." [Abstract]

Coudore-Civiale MA, Courteix C, Boucher M, Meen M, Fialip J, Eschalier A, Ardid D.
Potentiation of morphine and clomipramine analgesia by cholecystokinin -B antagonist CI-988 in diabetic rats.
Neurosci Lett 2000 May 26;286(1):37-40
"The aim of this study was to determine the influence of an intrathecally injected cholecystokinin-B (CCK-B) receptor antagonist, CI-988, on the analgesic effect of morphine and clomipramine in diabetic rats. Administered alone, morphine (0.1 mg/kg, i.v.) and clomipramine (3 mg/kg, i.v.) have respectively no effect and only a slight effect on vocalization thresholds to paw pressure in diabetic rats, but, when coadministered with CI-988 (0.1 microg/rat, i.t.), an appreciable antinociceptive effect was observed. This suggests that a spinal blockade of cholecystokininergic system increases the analgesia induced by morphine or clomipramine. A CCK-B receptor antagonist could thus be used to lower dosages of morphine or antidepressant drugs in the management of neuropathic pain in humans, and thereby reduce their side effects." [Abstract]

Strohle A, Holsboer F, Rupprecht R.
Increased ACTH concentrations associated with cholecystokinin tetrapeptide-induced panic attacks in patients with panic disorder.
Neuropsychopharmacology 2000 Mar;22(3):251-6
"Preclinical findings on the role of corticotropin releasing hormone (CRH) in stress and anxiety, on the interaction of CRH and cholecystokinin (CCK) in modulating anxiety, as well as the blunted corticotropin (ACTH) response to CRH in panic disorder suggest that CRH may play a role in panic disorder. To further characterize the role of the hypothalamic-pituitary-adrenocortical (HPA) system in panic disorder, we compared patients with and without CCK tetrapeptide (CCK-4) induced panic attacks. Twenty-four patients with panic disorder were given injections of CCK-4 (25 micrograms). Panic attacks, psychopathological changes, as well as ACTH and cortisol secretion were recorded. Fifteen of the 24 patients experienced a panic attack after CCK-4. ACTH secretion was significantly higher in the patients with CCK-4-induced panic attacks than in those without such attacks. The patients without CCK-4-induced attacks had a brief but less pronounced increase in ACTH concentrations. Cortisol concentrations were not significantly increased after CCK-4 administration. The increased ACTH concentrations suggest that the activation of the HPA system in CCK-4-induced panic attacks plays a physiological role. CRH may be involved in experimentally-occurring and perhaps in naturally-occurring panic attacks as well." [Abstract]

Shlik J, Zhou Y, Koszycki D, Vaccarino FJ, Bradwejn J.
Effects of CCK-4 infusion on the acoustic eye-blink startle and psychophysiological measures in healthy volunteers.
J Psychopharmacol 1999 Dec;13(4):385-90
"The acoustic startle response (ASR) and a range of psychophysiological parameters were evaluated during a continuous intravenous administration of cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. Subjects (n=28) were randomly assigned to double-blind infusion of either CCK-4 (0.5 mg/60 min) or placebo. The ASR sessions were performed prior to infusion and at 20 min and 50 min after the onset of infusion by recording eye-blink response to a series of acoustic stimuli (110 dB, 40 ms). An effect of CCK-4 on the eye-blink startle was observed in the first half of infusion. CCK-4 produced an increase of eye-blink startle amplitude from baseline values in contrast to the decrease observed at this time point with placebo. A mild increase in anxiety and heart rate followed by fatigue was reported with CCK-4. Administration of CCK-4 produced increases in plasma concentrations of adrenocorticotropic hormone, cortisol, prolactin and growth hormone. The results of this study show that a prolonged intravenous administration of CCK-4 may be a useful challenge method for further studies on the role of CCK system in the modulation of human anxiety and stress response." [Abstract]

Tsutsumi T, Akiyoshi J, Isogawa K, Kohno Y, Hikichi T, Nagayama H.
Suppression of conditioned fear by administration of CCKB receptor antagonist PD135158.
Neuropeptides 1999 Dec;33(6):483-6
"In order to examine the involvement of CCK in the formation of anxiety, we have investigated whether CCKB receptor antagonist PD135158 suppressed conditioned fear stress. Rats were individually subjected to 30 min of inescapable electric footshock in a chamber with a grid floor. First, the rats were individually subjected to 30 min of footshock. Twenty-four h after the footshock, the rats were again placed in the chamber and observed for 5 min without shocks. PD135158 was administered 30 min before placing the rats in the chamber again. Secondly, PD135158 was administered 30 min before footshock. Thirdly, PD135158 was administered 5 min after footshock. Administration of PD135158 30 min before conditioned fear stress significantly reduced freezing behavior. Administration of PD135158 30 min before footshock also significantly reduced freezing behavior. But, administration of PD135158 5 min after footshock did not significantly reduce freezing behavior. PD135158 blocked not only the acquisition but also the expression of conditioned fear. These results suggest that the CCKB receptor might play an important role in conditioned fear stress and that it might be related to anxiety." [Abstract]

Abelson JL, Liberzon I.
Dose response of adrenocorticotropin and cortisol to the CCK-B agonist pentagastrin.
Neuropsychopharmacology 1999 Oct;21(4):485-94
"Cholecystokinin (CCK) is an abundant neurotransmitter in brain. Its functional significance in humans is incompletely understood, but it may modulate activity in the hypothalamic-pituitary-adrenal (HPA) axis. To explore this hypothesis, we examined the effects of varying doses (0 to 0.8 microgram/kg) of the CCK-B agonist pentagastrin on adrenocorticotropin (ACTH) and cortisol release in healthy human subjects. We also examined anxiety, heart rate (HR), and blood pressure (BP) responses. Pentagastrin induced large (up to 520% increase over baseline), significant and very rapid, dose-dependent elevations in ACTH and cortisol levels. Significant elevations in HR and BP were seen at all doses, without clear dose-response relationships. Anxious distress and symptom responses were also somewhat dose dependent; but hormonal responses were more robustly linked to pentagastrin dose than to these subjective measures. The HPA axis response to the CCK-B agonist pentagastrin may be a direct pharmacological effect. Further work is needed to determine the mechanisms and the physiological significance of CCK-mediated modulation of the human neuroendocrine stress axis." [Abstract]

Becker C, Hamon M, Benoliel JJ.
Prevention by 5-HT1A receptor agonists of restraint stress- and yohimbine-induced release of cholecystokinin in the frontal cortex of the freely moving rat.
Neuropharmacology 1999 Apr;38(4):525-32
"In line with the idea that cholecystokinin (CCK) is involved in anxiety-related behaviours, previous investigations showed that stressful conditions and an 'anxiogenic' drug, yohimbine, increased the cortical release of CCK like-material (CCKLM) in awake rats, and that this effect could be prevented by diazepam. Here, we investigated whether other anxiolytic drugs such as 5-HT1A receptor agonists could also affect cortical CCKLM release. Indeed, neither buspirone (1 mg/kg i.p.), alnespirone (1 mg/kg i.p.) nor lesopitron (3 mg/kg i.p.) affected, on their own, CCKLM release. However, pretreatment with the latter drugs completely abolished the stimulatory effect of restraint stress on the peptide outflow. As expected of the involvement of 5-HT1A receptors, tertatolol (10 mg/kg i.p) markedly reduced the inhibitory effect of buspirone on restraint stress-evoked CCKLM overflow. On the other hand, pretreatment with buspirone, alnespirone or lesopitron also inhibited the stimulatory effect of yohimbine (5 mg/kg i.p.) on cortical CCKLM outflow. These data support the idea that the anxiolytic action of 5-HT1A receptor agonists could be mediated, at least partly, through their inhibitory influence on cortical CCK-ergic systems." [Abstract]

To CT, Bagdy G.
Anxiogenic effect of central CCK administration is attenuated by chronic fluoxetine or ipsapirone treatment.
Neuropharmacology 1999 Feb;38(2):279-82
"The effect of chronic fluoxetine and ipsapirone treatment on the anxiogenic effect of centrally administered cholecystokinin (CCK) was studied in the social interaction test in male Sprague-Dawley rats. Intracerebroventricular injection of unsulfated CCK-8 significantly decreased total interaction time and locomotor activity and caused some increase in selfgrooming and a reduction in rearing behaviour in a familiar arena in low light conditions. The selective serotonin reuptake inhibitor antidepressant fluoxetine alone (5 mg/kg, i.p.) also had clear acute anxiogenic actions (decrease in total interaction time, locomotor activity, rearing, increase in selfgrooming) after single dosing, but all these effects were omitted after chronic (3 weeks) treatment. In contrast, a single injection of the 5-HT1A receptor partial agonist ipsapirone (5 mg/kg, i.p.) alone had only motor effects (decrease in selfgrooming and rearing), and these effects were preserved after chronic treatment. Chronic fluoxetine treatment (5 mg/kg per day, 3 weeks) abolished the effects of CCK-8 (1 nmol/rat, i.c.v.). Chronic treatment with ipsapirone (5 mg/kg per day, 3 weeks) partially attenuated the effects of CCK-8 (1 nmol/rat, i.c.v.). Our studies provide further evidence for a 5-HT/CCK interaction in the regulation of anxiety." [Abstract]

Akiyoshi J, Yamauchi C, Furuta M, Katsuragi S, Kohno Y, Yamamoto Y, Miyamoto M, Tsutsumi T, Isogawa K, Fujii I.
Relationship between SCL-90, Maudsley Personality Inventory and CCK4-induced intracellular calcium response in T cells.
Psychiatry Res 1998 Dec 14;81(3):381-6
"This study examined the relationship between the Symptom Checklist 90 (SCL-90), Maudsley Personality Inventory (MPI) and cholecystokinin 4 (CCK4)-induced intracellular calcium response in T cells. Fifty-two normal volunteers were 37 males and 15 females; they ranged in age from 23 to 44 years. Measures included CCK4-induced intracellular calcium response in T cells, SCL-90 scores, and MPI. Paranoid ideation and interpersonal sensitivity in SCL-90 showed a significant negative association with CCK4-induced intracellular calcium response. Absent were sex differences and extroversion and neuroticism correlations. There were no significant differences between men and women in SCL-90 or MPI scores. There was no correlation among extroversion and neuroticism and CCK4-induced intracellular calcium response. CCKB receptor function might play a role in paranoid ideation and interpersonal sensitivity." [Abstract]

Greenough A, Cole G, Lewis J, Lockton A, Blundell J.
Untangling the effects of hunger, anxiety, and nausea on energy intake during intravenous cholecystokinin octapeptide (CCK-8) infusion.
Physiol Behav 1998 Nov 15;65(2):303-10
"Infusions of cholecystokinin (CCK) may exert their effects on appetite by inducing feelings of nausea or anxiety. In this double blind, placebo controlled crossover study, the impact of these effects on appetite were examined. Fifteen male subjects received a 20 min i.v. infusion of cholecystokinin octapeptide (CCK-8) (4 ng/kg/min) or saline. The infusion commenced 20 min after a soup preload and 10 min before an ad libitum test meal. Visual analogue scales of appetite and mood were measured over 3 h, and subjects were instructed to report any other sensations they experienced over this time. CCK-8 significantly reduced premeal hunger, elevated premeal anxiety, and reduced energy intake at the ad libitum test meal. Meal duration and rate of eating (kcal/min) were also significantly reduced after CCK-8. After the smaller meal with CCK-8, hunger rose quickly to a higher level than with placebo. The return of hunger was commensurate with the smaller amount of energy consumed and indicated that CCK did not exert an enduring effect on hunger suppression. A significant correlation was found between the reduction in energy intake and hunger (r = 0.75 p < 0.01), but not with anxiety (r = 0.15 not significant). Analyses were performed separately on subjects who did (n = 8), or did not (n = 7) report gastrointestinal disturbance. Energy intake was reduced by 56.6% and 44.6%, respectively. These results indicate that, although feelings of anxiety and nausea may accompany CCK infusions, they are not necessary for the effects of CCK on appetite. These data provide support for a role of CCK in satiety." [Abstract]

Harada S, Okubo T, Tsutsumi M, Takase S, Muramatsu T.
A new genetic variant in the Sp1 binding cis-element of cholecystokinin gene promoter region and relationship to alcoholism.
Alcohol Clin Exp Res 1998 May;22(3 Suppl):93S-96S
"Neuropeptide cholecystokinin (CCK) and the CCK receptors in the central nervous system mediate actions on increasing firings, anxiety, and nociceptions. Furthermore, CCK modulates the release of dopamine and dopamine-related behaviors in the mesolimbic pathway. In our study, genetic variation in the promoter and coding regions of the prepro-CCK gene were analyzed among 66 Japanese, 66 American Whites, 54 Chinese, and 41 Colombian natives. Two nucleotide sequence variants were found: a frequent mutation at nucleotide position -45 C to T involved in core sequence of Sp1 binding cis-element of the promoter region, and a C to T substitution at the 1662 position in intron 2. Analysis for the segregation study in 10 families of twins confirmed codominant heredity of two alleles. Distribution of genotypes and gene frequencies of 66 controls and 108 alcoholics in Japan presented that allelic variant T type in alcoholics was found in higher frequencies than that of controls, and distribution of these genotypes was significantly different between the both groups." [Abstract]

Valverde O, Roques BP.
Cholecystokinin modulates the aversive component of morphine withdrawal syndrome in rats.
Neurosci Lett 1998 Mar 6;244(1):37-40
"The conditioned place aversion paradigm was used to investigate the role of cholecystokinin in the aversive/dysphoric component of morphine abstinence. Several cholecystokinin ligands were chronically administered during the development of morphine dependence: the CCKA antagonist devazepide, the CCKB antagonists PD-134,308 and L-365,260, and the CCKB agonist BC 264. The CCK-B antagonists L-365,260 and PD-134,308 decreased and completely blocked (respectively) the place aversion induced by naloxone in morphine dependent animals whereas BC 264 and devazepide were inactive in this model. No effect was observed in non-dependent animals after chronic administration of these CCK-ligands. These results show a distinct role for CCK receptors in the regulation of the motivational component of morphine abstinence, probably related to their differential effects in the regulation of limbic dopaminergic neurons." [Abstract]

Hebb AL, Zacharko RM.
Central D-Ala2-Met5-enkephalinamide mu/delta-opioid receptor activation reverses the anxiogenic-like properties of cholecystokinin on locomotor and rearing activity in CD-1 mice.
Brain Res. 2003 Apr 25;970(1-2):9-19.
"There is evidence to suggest an antagonistic interaction between the anxiogenic peptide, cholecystokinin (CCK) and the anxiolytic opioid peptide, enkephalin in mesolimbic sites following stressor applications in humans and animals which may define specific behavioral symptom subsets and alter the course of anxiety-like behavior. Locomotor and rearing behavior were decreased following a central CCK-8S (50 ng) injection among independent groups of mice relative to saline-treated animals. Central administration of DALA not only ameliorated the CCK-induced behavioral deficits but exaggerated behavioral activity of CCK and saline control mice (SAL). Locomotor activity and rearing behavior were depressed 24 h following DALA administration yet returned to basal values 168 h following drug applications. Eighteen days following the initial 50 ng CCK-8S and intervening DALA challenge, mice were administered 5 ng CCK-8S. An intervening dose of DALA in mice following the original 50 ng CCK-8S administration on Day 1 was associated with elevated locomotor activity in mice in response to the 5 ng CCK-8S challenge on Day 18. In contrast to locomotor activity, mice administered DALA following the original 50 ng CCK-8S administration on Day 1 demonstrated decreased rearing behavior to both 5 ng CCK-8S challenge and SAL on Day 18. Moreover, administration of 5 ng CCK-8S on Day 18 was associated with decreased rearing behavior in mice previously administered SAL on Day 1. These data imply that while CCK induces relatively protracted behavioral disturbances, mu/delta receptor activation may change the course of psychopathology." [Abstract]

Huston JP, Schildein S, Gerhardt P, Privou C, Fink H, Hasenohrl RU.
Modulation of memory, reinforcement and anxiety parameters by intra-amygdala injection of cholecystokinin-fragments Boc-CCK-4 and CCK-8s.
Peptides 1998;19(1):27-37
"This series of experiments examined the effects of the cholecystokinin (CCK) fragments Boc-CCK-4 and CCK-8s on memory, reinforcement and anxiety following unilateral injection into the central nucleus of the amygdala (CeA). In experiment 1, rats with chronically implanted cannulae were injected with CCK-8s or Boc-CCK-4 and were tested on a one-trial uphill avoidance task. Post-trial injection of 20 ng Boc-CCK-4 or 1 ng CCK-8s was found to improve the retention performance, whereas lower and higher doses had no effect. The hypermnestic effects of Boc-CCK-4 and CCK-8s were no longer evident when injection was performed 5 h, rather than immediately, after the learning trial. In experiment 2, the elevated plus-maze was used to gauge anxiogenous properties of intra-amygdala injections of Boc-CCK-4 and CCK-8s in memory-enhancing doses. The treatment with 20 ng Boc-CCK-4 and 1 ng CCK-8s did not influence the number of entries into and time spent on the open and enclosed arms of the maze as well as other anxiety-related behaviors. In experiment 3, possible reinforcing effects of the CCK-fragments were examined. After intra-amygdala injection of Boc-CCK-4 or CCK-8s in memory-enhancing doses the rats were placed into one of four restricted quadrants of a circular open field (closed corral) for a single conditioning trial. Subsequent tests for conditioned corral preference revealed no evidence for reinforcing or aversive effects of the CCK-fragments. In sum, these findings indicate that Boc-CCK-4 and CCK-8s facilitate memory processing upon injection into the CeA without exerting reinforcing or anxiogenous effects." [Abstract]

MacNeil G, Sela Y, McIntosh J, Zacharko RM.
Anxiogenic behavior in the light-dark paradigm follwoing intraventricular administration of cholecystokinin-8S, restraint stress, or uncontrollable footshock in the CD-1 mouse.
Pharmacol Biochem Behav 1997 Nov;58(3):737-46
"The influence of restraint stress (0, 15, 30, or 60 min), uncontrollable footshock (0, 15, 30, or 60 shocks), or intraventricular CCK-8S administration (0, 5, 25, or 50 ng delivered in a 1 microliter volume) were evaluated on transition frequency and cumulative time in light among CD-1 mice in the light-dark paradigm. Mice exposed to restraint stress of either 15 or 60 min were indistinguishable from nonrestrained animals, while the 30-min session of restraint decreased time in light and transition scores. The presentation of 15, 30, or 60 uncontrollable footshocks were equally effective in decreasing cumulative time in light but had no effect on transition scores. Intraventricular infusion of 25 and 50 ng doses of cholecystokinin-8S reduced cumulative time in light and transition frequency in CD-1 mice relative to vehicle or 5 ng CCK-8S-treated animals in the light-dark paradigm. The time in light and transition data secured among mice with repeated light-dark exposure and 30 min of restraint were comparable to the corresponding scores secured when performance was only evaluated on trial 1. Transition scores were reduced on trial 1 of mice exposed to 30 min of footshock, but time in light was reminiscent of the performance detected among mice with prior light-dark experience." [Abstract]

Rex A, Marsden CA, Fink H.
Cortical 5-HT-CCK interactions and anxiety-related behaviour of guinea-pigs: a microdialysis study.
Neurosci Lett 1997 Jun 6;228(2):79-82
"Serotonin (5-HT) and cholecystokinin (CCK) are involved in the development of anxiety. There are only few data suggesting interactions between CCK and 5-HT under aversive conditions. In our study the cholecystokinin tetrapeptide (CCK-4) (10 microg/kg) induced 'anxious' behaviour and potentiated the increase of 5-HT release on the elevated plus maze (X-maze). The 'anxiolytic' 5-HT1A agonist 8-hydroxy-2-(di-n-propyl amino) tetralin (8-OH-DPAT; 0.3 mg/kg) reduced basal 5-HT and the increase in 5-HT release on the X-maze. 8-OH-DPAT given simultaneously with CCK-4, blocked the effects of CCK-4. The results demonstrate an interaction between CCK and 5-HT1A mechanisms via the influence on cortical 5-HT release." [Abstract]

Matto V, Harro J, Allikmets L.
The effect of drugs acting on CCK receptors and rat free exploration in the exploration box.
J Physiol Pharmacol 1997 Jun;48(2):239-51
"The effects of cholecystokinin (CCK) CCKA receptor antagonist devazepide (10 micrograms/kg and 1.0 mg/kg), CCKB receptor antagonist L 365260 (1.0 mg/kg), and CCKB receptor agonist CCK tetrapeptide (CCK-4, 75 micrograms/kg), and their concomitant administration with antidepressants desipramine (10 mg/kg) and citalopram (10 mg/kg) on rat exploratory behaviour were studied in the recently developed exploration box test. In addition, the effects of repeated administration of despiramine (10 mg/kg) and citalopram (10 mg/kg) were studied. After acute administration, CCK-4 decreased significantly the number of line crossings, rears, investigative approaches, and the time spent exploring. The time of latency and the number of entries into large arena were unchanged. Desipramine reduced all observed criterions of rat behaviour, but citalopram was ineffective. Devazepide (1.0 mg/kg) and L 365260 (1.0 mg/kg) had no effect on rat behaviour after acute or repeated administration. L 365260 (1.0 mg/kg) blocked the antiexploratory effect of CCK-4, whereas devazepide (10 micrograms/kg) did not. No interaction of CCK-4, devazepide, or L 365260 treatment with antidepressant treatment was found. Our results suggest that the administration of a CCKB agonist diminishes rat exploratory behaviour, but neither CCKA nor CCKB receptor blockade induces changes on rat exploratory behaviour in the free exploration paradigm." [Abstract]

Adamec RE, Shallow T, Budgell J.
Blockade of CCK(B) but not CCK(A) receptors before and after the stress of predator exposure prevents lasting increases in anxiety-like behavior: implications for anxiety associated with posttraumatic stress disorder.
Behav Neurosci 1997 Apr;111(2):435-49
"Lasting increases in anxiety-like behavior (ALB) in rodents in the elevated plus maze have been reported to follow brief (5 min) exposures to a cat. This study examined the role of CCK(A) and CCK(B) receptors in lasting increases in ALB following exposure to a cat. Block of CCK(B) receptors 30 min before and after cat exposure prevented increases in ALB assessed 1 week later in the elevated plus maze. Blocks of CCK(A) receptors either before or after cat exposure were without effect on increases in ALB measured 1 week later. Changes in activity or exploration could not account for the results. Effects of cat exposure on ALB, startle, and corticosteroid levels have been proposed as a model of affective disorder in posttraumatic stress disorder (PTSD). Implications of these findings for mechanisms of initiation of anxiety in PTSD and posttrauma pharmacological prophylaxis in PTSD are discussed." [Abstract]

Aluoja A, Shlik J, Vasar V, Kingisepp PH, Jagomagi K, Vasar E, Bradwejn J.
Emotional and cognitive factors connected with response to cholecystokinin tetrapeptide in healthy volunteers.
Psychiatry Res 1997 Jan 15;66(1):59-67
"This article examines the effect of baseline anxiety, anxiety sensitivity and dysfunctional attitudes on the response to cholecystokinin tetrapeptide (CCK-4) in healthy volunteers. CCK-4 and placebo were administered to 14 subjects in a double-blind manner. Four volunteers experienced a panic attack after CCK-4 administration. Those subjects who panicked had significantly higher baseline scores on dysfunctional attitudes. Dysfunctional thought patterns appeared also to predict number of symptoms and experience of cognitive and affective symptoms during injection. Baseline anxiety as well as anxiety sensitivity predicted reactions to placebo but not panic responses to CCK-4. Results suggest that a general tendency towards erroneous interpretation of information has some role in mediating the panicogenic effects of CCK-4, and also interpersonal sensitivity may constitute a vulnerability factor for panic. Psychological factors that have been considered more specific to panic disorder, namely high state and trait anxiety as well as anxiety sensitivity, appeared mainly to determine general reactions to a threatening situation." [Abstract]

Frankland, Paul W., Josselyn, Sheena A., Bradwejn, Jacques, Vaccarino, Franco J., Yeomans, John S.
Activation of Amygdala CholecystokininB Receptors Potentiates the Acoustic Startle Response in the Rat
J. Neurosci. 1997 17: 1838-1847
"The acoustic startle reflex is a sensitive index of "anxiety" and "fear." Potentiation of startle by conditioned and unconditioned fear stimuli appears to be mediated by the amygdala. CholecystokininB (CCKB) agonists increase "anxiety" in laboratory animals and induce "panic" in humans. Here, we investigate the role CCKB receptor-mediated mechanisms in the amygdala in the potentiation of startle. First, intra-amygdala infusions of the CCKB receptor agonist pentagastrin (0, 0.01, 0.1, 1, and 10 nM) produced a dose-related potentiation of acoustic startle responses. At the highest dose, startle amplitudes were increased up to 90% above preinfusion baseline levels. Second, similar infusions of pentagastrin had no effect on locomotor activity over the same time course, showing that increases in startle responsivity after infusions of pentagastrin are not attributable to nonspecific changes in motor activity. Third, infusions of similar doses of pentagastrin into the striatum or nucleus accumbens did not potentiate startle responses. Fourth, pretreatment with the CCKB receptor antagonist L-365,260 (0.1 mg/kg, i.p.) attenuated the potentiation of startle produced by intra-amygdala infusions of pentagastrin. Finally, intra-amygdala infusion of the CCKB receptor-selective antagonist PD-135158 (10 µg) blocked the potentiation of startle produced by i.c.v. infusions of pentagastrin, suggesting that i.c.v. infusions of pentagastrin potentiate startle responses via activation of amygdala CCKB receptors. These results show that amygdala CCKB receptor-mediated mechanisms are involved in the potentiation of acoustic startle responses." [Full Text]

McLean HA, Champagnat J, Denavit-Saubie M.
A cholecystokinin-B receptor antagonist potentiates GABAergic and glycinergic inhibition in the nucleus of the solitary tract of the rat.
Eur J Neurosci 1996 Jun;8(6):1078-84
"In both rodent and primate in vivo models, cholecystokininB (CCKB) antagonists such as PD134,308 have anxiolytic effects that may involve the potentiation of GABAergic transmission. We have investigated this interaction using exogenous application of GABA and whole cell patch recording techniques in neurons of the nucleus of the solitary tract (NTS) in brainstem slice preparations. In the presence of PD143,308 the magnitude of the GABA-evoked decrease in membrane input resistance was enhanced by 41.2 +/- 3.1% and the duration of the response was prolonged by 34.8 +/- 2.2%. Also, PD134, 308 potentiated glycine-evoked decreases in membrane input resistance, increasing the amplitude of the response by 62.8 +/- 4. 85 and prolonging the duration of the response by 23.5 +/- 3.6%. The effect of PD134,308 persisted in the presence of tetrodotoxin, after reversal of the transmembrane gradient of chloride ions and under conditions of exaggerated GABAA receptor desensitization. Our results demonstrate that at least part of the functional link between PD134,308 and the GABAA response occurs postsynaptically." [Abstract]

Rotzinger S, Vaccarino FJ.
Cholecystokinin receptor subtypes: role in the modulation of anxiety-related and reward-related behaviours in animal models.
J Psychiatry Neurosci. 2003 May;28(3):171-81.
"Cholecystokinin (CCK) is an abundant and widely distributed neuropeptide that plays a modulatory role in a variety of behaviours. This paper focuses on the role of CCK in modulating anxiety-related and reward-related behaviours in key brain regions of the amygdala and mesolimbic dopamine system, respectively. The role of CCK in mediating aspects of these behaviours has been studied in a variety of behavioural paradigms, but inconsistent results have led to confusion regarding the precise role of the receptor subtypes in mediating behaviour. The confusion in the literature may come in part from the diverse behavioural paradigms that are used, the differences in regional effects of CCK manipulations in different areas and at different receptor subtypes in these areas and the dependence of the behavioural outcome on the baseline state of arousal of the animal. Evidence on the role of CCK in anxiety-related and reward-related behaviours in various animal models indicates that CCK-B receptors in the basolateral amygdala are important mediators of anxiety-related behaviours and that CCK-A and CCK-B receptors in the nucleus accumbens are important in mediating different aspects of reward-related behaviour. Emphasis is placed upon the role of CCK as a neuromodulator that is recruited only under conditions of high frequency neuronal firing." [Abstract/Link to PDF]

Josselyn SA, Franco VP, Vaccarino FJ.
PD-135158, a CCKB receptor antagonist, microinjected into the nucleus accumbens and the expression of conditioned rewarded behavior.
Neurosci Lett 1996 May 10;209(2):85-8
"Cholecystokinin (CCK) has been localized in the nucleus accumbens (NAC) where it may interact with dopamine neurotransmission. NAC dopamine is involved in the control over behavior produced by conditioned rewards. The present experiment examines whether the blockade of CCKB receptors in the NAC with microinjection of PD-135158 (10 micrograms in 0.5 microliter) potentiates bar-pressing for stimuli previously associated with food reward. Intra-NAC microinjections of amphetamine (10 micrograms in 0.5 microliter) increased the number of bar presses for conditioned reward presentation. Furthermore, similar administration of PD-135158 produced no significant effect on responding when administered alone but potentiated the level of amphetamine responding. These findings suggest that endogenous CCKB mechanisms in the NAC may normally inhibit dopamine function in reward-related behaviors." [Abstract]

Koszycki D, Zacharko RM, Bradwejn J.
Influence of personality on behavioral response to cholecystokinin-tetrapeptide in patients with panic disorder.
Psychiatry Res 1996 May 17;62(2):131-8
"The relationship between personality, as measured by selected clinical scales of the Minnesota Multiphasic Personality Inventory (MMPI) (Hypochondriasis, Depression, Hysteria, Psychasthenia, Social Introversion, and Anxiety) and the Anxiety Sensitivity Index (ASI), and behavioral response to the panicogenic agent cholecystokinin-tetrapeptide (CCK-4) was examined in 29 patients with panic disorder with or without agoraphobia. Significant correlations were found between the MMPI Social Introversion scale and somatic, cognitive, and affective response to CCK-4. Both the MMPI Anxiety scale and the ASI correlated significantly with cognitive response to CCK-4, but not with somatic or affective response. None of the other selected MMPI clinical scales correlated with response to CCK-4. Multiple regression analyses identified the MMPI Social Introversion scale as the best predictor of all three indices of panic-anxiety induced by CCK-4. The results suggest that the relationship between neurotic introversion and sensitivity to CCK requires closer scrutiny." [Abstract]

Harro J, Oreland L, Vasar E, Bradwejn J.
Impaired exploratory behaviour after DSP-4 treatment in rats: implications for the increased anxiety after noradrenergic denervation.
Eur Neuropsychopharmacol 1995 Dec;5(4):447-55
"The effect of DSP-4, a neurotoxin selectively affecting the projections of the locus coeruleus, upon exploratory behaviour of rats was studied in a complex exploration test, including a choice between open and enclosed areas and both inquisitive and inspective exploration elements. One week after DSP-4 (50 mg/kg i.p.) administration, the neurotoxin-treated rats did not explore a novel open area to any extent on the first exposure to the apparatus; however, on the third day of testing, these animals began to explore the area and the novel objects. Diazepam (0.5 mg/kg) treatment did not change the behaviour of control rats, but significantly increased the exploratory activity of the DSP-4-treated animals. LY 288513, a selective CCKB receptor antagonist (0.01 mg/kg), prevented the increase in exploratory activity in the DSP-4-treated rats, but increased the exploratory activity of controls on the third exposure to the test situation. The results of this investigation suggest that DSP-4 treatment reduces neotic behaviour by increasing neophobia rather than by decreasing exploratory drive. The divergence reported between the relative potencies of CCKB receptor antagonists in exploratory activity and other anxiety tests may in part be due to the effects of these drugs on exploratory drive." [Abstract]

Harro J, Jossan SS, Oreland L.
Changes in cholecystokinin receptor binding in rat brain after selective damage of locus coeruleus projections by DSP-4 treatment.
Naunyn Schmiedebergs Arch Pharmacol 1992 Oct;346(4):425-31
"Brain cholecystokinin (CCK)- and noradrenergic activities are two neurochemical systems implicated in anxiety and deficits in novelty-related behaviour. In order to clarify a possible interaction between CCK- and noradrenergic neurotransmission in the brain, DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a neurotoxin that selectively destroys noradrenaline-containing nerve terminals originating from the locus coeruleus, was administered to rats IP (10 and 50 mg/kg) seven days before decapitation. Noradrenaline uptake was very markedly reduced in the frontal cortex and hippocampus of the DSP-4 treated animals, whereas the decrease in the hypothalamus was smaller but still statistically significant. Dopamine uptake in the corpus striatum, as well as serotonin uptake in the frontal cortex, hippocampus and hypothalamus, were not influenced by DSP-4 treatment. Concomitantly, CCK receptor binding in certain brain regions was markedly affected. Thus, CCK receptor density was significantly higher in the frontal cortex and hippocampus of DSP-4-treated rats. If desipramine (25 mg/kg) was administered before DSP-4 treatment, the DSP-4-induced changes both in noradrenaline uptake and CCK receptor binding were not present, suggesting that both effects were exerted after uptake of the neurotoxin by the nerve terminals. The time-course of the development of changes in CCK-8 binding paralleled with some lag the development of changes in noradrenaline uptake. These findings demonstrate the denervation of noradrenergic input from the locus coeruleus induces certain alterations in the CCKergic neurotransmission. These alterations are similar to those seen in rats with deficits in response to novel stimuli, and may therefore mediate the neophobic responses observed in animals after lesions of noradrenergic innervation of the forebrain." [Abstract]

Kramer MS, Cutler NR, Ballenger JC, Patterson WM, Mendels J, Chenault A, Shrivastava R, Matzura-Wolfe D, Lines C, Reines S.
A placebo-controlled trial of L-365,260, a CCKB antagonist, in panic disorder.
Biol Psychiatry 1995 Apr 1;37(7):462-6
"The functional role of cholecystokinin in the central nervous system is unknown. The tetra peptide CCK-4 was previously observed to induce panic attacks in a majority of normal volunteers and patients with panic disorder. Furthermore, it had been demonstrated that pretreatment with 10-50 mg of L-365,260, a selective CCKB antagonist, blocked CCK-4 induced panic in patients with panic disorder. Therefore, the present multicenter, placebo-controlled, double-blind trial was designed to investigate the efficacy of L-365,260, a CCKB antagonist, in patients with panic disorder with or without agoraphobia. Following a 1-week, single-blind placebo period, 88 patients were randomized to double-blind treatment in which they received either L-365,260, 30 mg qid, or placebo for 6 weeks. At the dose tested, there were no clinically significant differences between L-365,260 and placebo in global improvement ratings, Hamilton anxiety rating scale scores, panic attack frequency, panic attack intensity, or disability measures. The possible reasons for lack of effect with L-365,260 are discussed." [Abstract]

Lines C, Challenor J, Traub M.
Cholecystokinin and anxiety in normal volunteers: an investigation of the anxiogenic properties of pentagastrin and reversal by the cholecystokinin receptor subtype B antagonist L-365,260.
Br J Clin Pharmacol 1995 Mar;39(3):235-42
"1. Two studies were undertaken to develop a model of experimentally induced anxiety in normal volunteers based on cholecystokinin (CCK) receptor agonism/antagonism. 2. In Study 1 rapid intravenous injections of the CCK receptor subtype B (CCKB) agonist pentagastrin (0.15, 0.3 and 0.6 micrograms kg-1) were found to produce dose-related increases in subjective ratings of anxiety compared with placebo. 3. In Study 2 the effects of pre-treatment with two doses of the CCKB receptor antagonist L-365,260 (10 mg, 50 mg p.o.) on the anxiety induced by pentagastrin 0.3 micrograms kg-1 i.v. were investigated. Detailed measurements of blood pressure and pulse rate were also undertaken. Pentagastrin produced changes in blood pressure and pulse rate which had a similar time course to that observed for subjective anxiety ratings. L-365,260 reversed both the autonomic and anxiogenic effects of pentagastrin. 4. The pentagastrin model would appear to be a useful tool for investigating potential anxiolytics in normal volunteers." [Abstract]

Ladurelle N, Roques BP, Dauge V.
The transfer of rats from a familiar to a novel environment prolongs the increase of extracellular dopamine efflux induced by CCK8 in the posterior nucleus accumbens.
J Neurosci 1995 Apr;15(4):3118-27
"The effects of cholecystokinin octapeptide (CCK8) on extracellular dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, were measured in the nucleus accumbens (N. Acc.). The experiments were carried out using in vivo microdialysis in awake rats submitted, or not, to a novel environment, the four-hole box. The exploratory behavior of the animals was studied concurrently in these boxes and in the elevated plus maze. Without CCK8 treatment, the transfer of animals from their home cages to the four-hole box induced a transient increase in DA efflux and also tended to increase its metabolites in the posterior N. Acc. In rats placed in a familiar environment, the administration of 25 pmol of CCK8 in this region immediately enhanced DA release, with levels rapidly returning to normal at the end of the perfusion. In contrast, this treatment produced a longer effect in rats transferred to the four-hole box, since the DA efflux was still increased 80 min after the removal of CCK8. The intra-accumbal administration of CCK8 induced a hypoexploration in the four-hole box. Moreover, an anxiogenic-like effect of CCK8 was found in the elevated plus maze, only in rats submitted to a novel environment (four-hole box). These data show that (1) the postero-accumbens DA neurons can be activated by environmental changes and (2) that the intensity of the CCK8 effects on extracellular DA levels and on anxiety-like responses seems to depend on the activity of these neurons previous to CCK8 treatment. The prolonged DA release induced by CCK8 in animals placed in a new situation could correspond to a biochemical anticipation preparing them to react when faced by another stimulus." [Abstract]

Derrien M, McCort-Tranchepain I, Ducos B, Roques BP, Durieux C.
Heterogeneity of CCK-B receptors involved in animal models of anxiety.
Pharmacol Biochem Behav 1994 Sep;49(1):133-41
"The effects of the selective CCK-B agonists, BC 264 and BC 197, and the nonselective CCK agonist BDNL were investigated in the elevated plus-maze in rats. BDNL and BC 197 induced anxiogeniclike effects, in contrast to BC 264, which had no effect. The behavioral responses induced by BDNL were not significantly blocked by L-365,260, but were suppressed by CI-988, another selective CCK-B antagonist, and by high doses of L-364,718, a selective CCK-A antagonist. BC 197-induced effects were also blocked by CI-988. Competition experiments performed with [3H]pBC 264 using brain membranes of guinea pig, mouse, and rat were significantly better fitted when analyzed by a two site model than by a one site model with BC 197 but not with BC 264. Moreover, BC 264 produced anxiogeniclike effects when administered with increasing doses of L-365,260 and opposing effects with increasing doses of CI-988. Together these results give pharmacological and behavioral evidence for the existence of CCK-B receptor subtypes." [Abstract]

Belcheva I, Belcheva S, Petkov VV, Petkov VD.
Asymmetry in behavioral responses to cholecystokinin microinjected into rat nucleus accumbens and amygdala.
Neuropharmacology 1994 Aug;33(8):995-1002
"The behavioral responses of rats to uni- or bilateral microinjections of the octapeptide cholecystokinin (CCK-8) into the left and/or right or both nucleus accumbens (NA) or amygdalae were studied. There were two main findings of effects of microinjections of CCK-8 into NA. First, bilateral injections of CCK-8 into NA dose-dependently decreased the horizontal activity. The second more important finding was that CCK-8 at a specific dose (0.01 micrograms) injected into the right NA increased the number of horizontal movements 6-fold as compared to the injection into the left NA. Neither uni- nor bilateral injections of CCK-8 into NA at all doses used induced changes in the vertical movements. CCK-8 injected into left, right or both amigdalae increased locomotion at the lowest dose (0.01 microgram), while at the high doses (0.5 and 1.0 microgram) it significantly decreased it. The plus-maze test confirmed the anxiogenic effect of CCK-8 (0.01 microgram) injected into amigdalae. CCK-8 exerted a favorable effect on learning and memory (shuttle-box) when injected into the left but not into the right amygdala. Injection of CCK-8 (0.01 micrograms) into left amygdala provoked a 4-fold increase of the number of avoidances as compared to the microinjection into the right amygdala." [Abstract]

Balschun D, Reymann KG.
Cholecystokinin (CCK-8S) prolongs 'unsaturated' theta-pulse induced long-term potentiation in rat hippocampal CA1 in vitro.
Neuropeptides 1994 Jun;26(6):421-7
"The effects of bath-applied sulphated cholecystokinin octapeptide (CCK-8S; 500 nM) and the selective CCKB receptor antagonist PD 135158 (1 microM) on the induction and maintenance of an 'unsaturated' long-term potentiation (LTP) were examined using recordings of field excitatory postsynaptic potentials (fEPSP) and population spikes (PS) in the hippocampal CA1 region of the rat. LTP was induced by a single theta-pulse stimulation (10 pulses at 7 Hz) of the Schaffer collateral-commissural pathway. CCK-8S had minor effects on the induction of LTP but substantially prolonged LTP of both fEPSP and PS from about 1 to at least 3 h. The antagonist PD 135158 had no influence on the induction of potentiation of fEPSP slope, but decreased the potentiation of PS amplitude. The results support the view that CCK-8S may facilitate long-term changes in glutamatergic synaptic transmission of the hippocampus, such as LTP." [Abstract]

Netto CF, Guimaraes FS.
Anxiogenic effect of cholecystokinin in the dorsal periaqueductal gray.
Neuropsychopharmacology. 2004 Jan;29(1):101-7.
"Systemic administration of cholecystokinin (CCK) fragments produces anxiogenic effects. The dorsal periaqueductal gray (dPAG) has been related to anxiety and panic reactions. The objective of this study was to investigate a possible anxiogenic effect of CCK-8 microinjected into the dPAG. At 10 min after the last microinjection (0.5 microl) into the dPAG male Wistar rats (N=7-17) were tested in the elevated plus-maze, an animal model of anxiety. The following treatments were tested alone or in combination: sulfated CCK-8 (CCK-8s, 0.5-1 microg), PD 135158 (N-methyl-D-glucamine, 0.1 microg), a CCK-2 receptor antagonist, lorglumide (0.1-0.3 microg), a CCK-1 receptor antagonist. In addition, Fos immunohistochemistry was performed in rats (n=3-4) treated with CCK-8s (1 microg) alone or in combination with PD 135158 (0.1 microg). CCK-8s produced anxiogenic-like effect, decreasing the percentage of time spent in open arm (saline=30.3+/-6.6, CCK 0.5 microg=15.2+/-1.8; CCK 1 microg=14.6+/-2.1). This effect was prevented by pretreatment with PD 135158, but not by lorglumide. CCK-8s injected into the dPAG induced Fos immunoreactivity in several brain areas related to defensive behavior, including the PAG, median, and dorsal raphe nuclei, superior colliculus, lateral septal nuclei, medial hypothalamus, and medial amygdala. This effect was also prevented by pretreatment with PD 135,158. These results suggest that CCK-8s, acting on CCK-2 receptors, may modulate anxiety reactions in the dPAG." [Abstract]

Liu H, Chandler S, Beitz AJ, Shipley MT, Behbehani MM.
Characterization of the effect of cholecystokinin (CCK) on neurons in the periaqueductal gray of the rat: immunocytochemical and in vivo and in vitro electrophysiological studies.
Brain Res 1994 Apr 11;642(1-2):83-94
"The periaqueductal gray (PAG) is an important integration site for pain, autonomic functions, vocalization, fear and anxiety. Cholecystokinin (CCK) is a major neurotransmitter in the PAG and CCK receptors are heterogeneously distributed within the PAG. Since CCK antagonists are anxiolytic and potentiate morphine analgesia, it is possible that these effects of CCK are mediated through alteration of neuronal activities in the PAG. The goals of this study were to examine the anatomical and physiological properties of the PAG CCK containing systems. The distribution of CCK-containing axons and boutons in PAG was examined using immunohistochemical procedures. These studies show that CCK-like immunoreactive (CCK-LIR) fibers and terminals are present throughout PAG, but are particularly heavily concentrated in a focal column that runs longitudinally throughout the rostrocaudal axis of dorsolateral PAG and in nucleus cuneiformis which represents a caudolateral extension of PAG. The physiological effects of CCK on PAG neurons were examined in both in vivo and in vitro preparations. In the in vivo experiments multibarreled electrodes were used to record from PAG neurons and to apply CCK and the CCK antagonists, CR1409 and proglumide. Of 37 neurons recorded in vivo, CCK caused excitation in 25 cells, inhibited 7 cells and had no effect on 5 cells. The excitatory effect was blocked by CR1409 in 11/11 cells tested. Proglumide blocked the excitatory response of CCK in 12/14 cells. Proglumide blocked the inhibitory effect in 2 of 7 cells, but CR1409 had no effect on CCK-evoked inhibition in 7 cells tested. Extracellular, conventional intracellular and whole cell patch clamping procedures were used to study CCK actions in the in vitro slice preparation. In the extracellular recording experiments, responses of PAG cells to CCK were measured in slices that were maintained at 22 degrees C (room temperature) and at 32 degrees C. CCK excited 40/56, inhibited 7/56 and had no effect on 9/56 cells; excitatory responses were blocked by CR1409 in 32/36 cells and by proglumide in 25/27 cells tested. Inhibitory responses to CCK were unaffected by CR1409, but were blocked in 3/7 cells by proglumide." [Abstract]

Rex A, Fink H, Marsden CA.
Effects of BOC-CCK-4 and L 365.260 on cortical 5-HT release in guinea-pigs on exposure to the elevated plus maze.
Neuropharmacology 1994 Mar-Apr;33(3-4):559-65
"The elevated plus maze is a well-established model of anxiety, with previous results showing that guinea-pigs handled daily from birth exhibit behaviour in this test similar to rats. In the present microdialysis study exposure of the guinea-pig to the elevated plus maze increased extracellular 5-HT in the lateral prefrontal cortex. The CCK-B receptor agonist BOC-CCK-4 (10 micrograms/kg) produced 'anxious' behaviour and potentiated the rise in 5-HT observed on exposure to the X-maze. The basal release of cortical extracellular 5-HT was not affected by BOC-CCK-4. Pretreatment with the selective CCK-B antagonist L 365.260 (100 micrograms/kg) antagonized both the 'anxious' behaviour and the neurochemical changes induced by BOC-CCK-4 while L 365.260 alone produced 'anxiolytic' behaviour, decreased basal extracellular 5-HT and prevented the increase in extracellular 5-HT seen when the guinea-pigs were exposed to the X-maze. Our results show that CCK-B receptor stimulation and blockade induce changes in central extracellular 5-HT levels associated with 'anxious' and 'anxiolytic' behaviour, respectively." [Abstract]

McCann UD, Slate SO, Geraci M, Uhde TW.
Peptides and anxiety: a dose-response evaluation of pentagastrin in healthy volunteers.
Anxiety 1994-95;1(6):258-67
"A large body of data suggest that brain cholecystokinin (CCK) systems are involved in the regulation of anxiety, and numerous studies have demonstrated that CCK-4, a CCKB agonist, reliably induces panic attacks in patients with panic disorder. Recently, pentagastrin, a commercially available CCKB agonist, has been reported to have similar anxiogenic properties. To further explore the utility of pentagastrin as a challenge agent and to determine whether its effects are dose-related, a dose-response study was conducted in ten healthy volunteers. Pentagastrin (0.2 microgram/kg, 0.6 microgram/kg and 1.0 microgram/kg) and inactive placebo were infused over one minute on four separate challenge days in a double-blind fashion. Subjects received pentagastrin while participating in a structured social interaction task. Repeated measures of anxiety, blood pressure, pulse, ACTH, and cortisol were taken at baseline and postinfusion. Pentagastrin administration led to increases in anxiety, pulse, ACTH, cortisol and physical symptoms of panic, in a dose-related manner. Participation in the social interaction task led to increases in measures of anxiety as well as increases in pulse and blood pressure. Few differences were found between the 0.2 microgram/kg dose of pentagastrin and placebo, or between the 0.6 microgram/kg and the 1.0 microgram/kg doses of pentagastrin. These findings support the notion that CCK systems are involved in the regulation of anxiety, and suggest that the 0.6 microgram/kg dose may be optimal for increasing symptoms of anxiety while minimizing unpleasant side effects. The powerful anxiogenic effects of the social interaction task underscore the importance of contextual variables in challenge studies." [Abstract]

Pavlasevic S, Bednar I, Qureshi GA, Sodersten P.
Brain cholecystokinin tetrapeptide levels are increased in a rat model of anxiety.
Neuroreport 1993 Dec 13;5(3):225-8
"Rats exposed to the smell of a predator adopted the freezing posture indicative of anxiety. Correlatively, the concentration of cholecystokinin tetrapeptide (CCK-4) was increased in the olfactory bulb, frontal and central cortex, dorsal and ventral striatum, central amygdala and the nucleus of the solitary tract. The concentration of CCK-8 was increased only in the ventral striatum. Glutamate was increased in the cortex and the striatum and dopamine was increased in the cortex. Intraperitoneal injection of CCK-4 increased brain levels of CCK-4 and replicated, in part, the behavioural effect of the smell of the predator. Injection of a CCK-B-receptor antagonist had the opposite behavioural effect. The results support a role for CCK-4 in anxiety." [Abstract]

Bradwejn J, Koszycki D, Annable L, Couetoux du Tertre A, Reines S, Karkanias C.
A dose-ranging study of the behavioral and cardiovascular effects of CCK-tetrapeptide in panic disorder.
Biol Psychiatry 1992 Nov 15;32(10):903-12
"Recent animal studies have shown that pretreatment with centrally active cholecystokinin (CCK) antagonists blocks the anxiogenic effects of CCK-tetrapeptide (CCK-4). In order to determine whether pretreatment with these antagonists can block the anxiogenic effects of CCK-4 in patients with panic disorder, a suitable challenge dose of CCK-4 must be selected. Thus, we conducted a dose range study in which patients with panic disorder (n = 29) were challenged with CCK-4 (10, 15, 20, or 25 micrograms) or placebo on two separate occasions, in a balanced incomplete block design. Patients received in random order 10 micrograms (n = 12), 15 micrograms (n = 11), 20 micrograms (n = 12), or 25 micrograms (n = 12) of CCK-4 or placebo (n = 11). CCK-4 induced anxiety and panic responses in a dose-dependent fashion. The incidence of panic attacks following the CCK-4 challenge was 17% (10 micrograms), 64% (15 micrograms), 75% (20 micrograms), and 75% (25 micrograms). None of the patients panicked with placebo. Moreover, a strong linear relationship between CCK-4 and increases in heart rate and diastolic blood pressure was found. The findings of this study suggest that a dose of 20 micrograms of CCK-4 (ED75) might be suitable for efficacy studies of CCKB antagonists and other potential antipanic drugs in patients with panic disorder." [Abstract]

Bradwejn J, Koszycki D, Shriqui C.
Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Clinical and behavioral findings.
Arch Gen Psychiatry 1991 Jul;48(7):603-10
"We studied the action of cholecystokinin tetrapeptide (CCK-4) in patients with panic disorder and normal controls. Subjects received, in random order, one injection of CCK-4 and one injection of placebo (saline) on two separate days in a double-blind crossover design. Two doses of CCK-4, 50 and 25 micrograms, were administered to two different samples of subjects. The panic rate with 50 micrograms of CCK-4 was 100% (12/12) for patients and 47% (7/15) for controls. The panic rate with 25 micrograms of CCK-4 was 91% (10/11) for patients and 17% (2/12) for controls. Nine percent of patients compared with 0% of controls panicked with placebo. These findings concur with previous reports of a panicogenic effect of CCK-4 and suggest that patients with panic disorder are more sensitive to the panicogenic effect of the peptide than are normal controls." [Abstract]

Costall B, Domeney AM, Hughes J, Kelly ME, Naylor RJ, Woodruff GN.
Anxiolytic effects of CCK-B antagonists.
Neuropeptides 1991 Jul;19 Suppl:65-73
"PD134308 and PD135158 are highly selective CCK-B receptor antagonists and were used to investigate the role of CCK-B receptors in aversive responding in rodent and primate models of anxiety. Both PD134308 and PD135158 were as effective as diazepam to antagonise aversive behaviour in the mouse light/dark discrimination test, in the rat social interaction and elevated X-maze tests, and in a marmoset 'human threat' model. However, the CCK-B antagonists were much more potent than diazepam and their effects were recorded over an extensive dose range. Furthermore, even at high doses, sedation or muscle relaxation was not observed and anxiogenesis was absent after withdrawal from a subchronic treatment. In contrast, withdrawal from drugs of abuse, diazepam, alcohol, cocaine and nicotine was associated with a withdrawal anxiogenesis that was completely prevented by PD134308 and PD135158. It is concluded that CCK-B receptors are involved in aversive-anxiety responding and that CCK-B receptor antagonists may provide a novel and improved approach to the treatment of anxiety and withdrawal from drugs of abuse." [Abstract]

Singh L, Field MJ, Vass CA, Hughes J, Woodruff GN.
The antagonism of benzodiazepine withdrawal effects by the selective cholecystokininB receptor antagonist CI-988.
Br J Pharmacol 1992 Jan;105(1):8-10
"The ability of a selective cholecystokininB (CCKB) receptor antagonist, CI-988, to block benzodiazepine withdrawal effects was examined in mice. The discontinuation of twice daily administration of diazepam (1 mg kg-1, i.p.) induced withdrawal anxiogenesis and a proconvulsant effect. In contrast, no such effects were seen following withdrawal from similar administration of CI-988. However, CI-988 dose-dependently (0.001-1.0 mg kg-1, s.c.) antagonized both the anxiogenesis and the proconvulsant effect following diazepam-withdrawal." [Abstract]

Powell KR, Barrett JE.
Evaluation of the effects of PD 134308 (CI-988), a CCK-B antagonist, on the punished responding of squirrel monkeys.
Neuropeptides 1991 Jul;19 Suppl:75-8
"Lever pressing of squirrel monkeys was maintained by a fixed-interval 3-min schedule of food presentation during which every 30th response also produced a brief electric shock. Lever pressing was suppressed during this stimulus (conflict or punishment) compared to that occurring prior to the introduction of shock or, with some monkeys, during an alternate stimulus in which punishment did not occur. PD 134308 (CI-988), administered i.m. (0.03-3.0 mg/kg), increased punished responding but had no effect on non-punished responding. Peak increases of 150% of control occurred at 3.0 mg/kg. There was no indication of sedation at the highest dose of PD 134308 (10.0 mg/kg). By comparison, chlordiazepoxide (1.0-10 mg/kg, i.m.) produced similar effects, except the magnitude of increases in punished responding reached approximately 200% of control performance levels and the higher doses reduced non-punished response rates. PD 134308 produces anxiolytic-like effects in this animal model of anxiety that would suggest potential clinical efficacy in humans of a novel class of compounds with actions at or modulated by cholecystokinin receptors." [Abstract]

Abelson JL.
Cholecystokinin in psychiatric research: a time for cautious excitement.
J Psychiatr Res 1995 Sep-Oct;29(5):389-96
"Cholecystokinin (CCK) is a peptide neurotransmitter that was originally isolated from the gastrointestinal system, but which is extensively and abundantly distributed within the central nervous system (CNS). Stimulated by the fairly recent recognition of receptor subtypes (A and B), and the development of receptor-specific antagonists, CCK research has been advancing rapidly; and its potential importance to psychiatric neuroscience has been increasingly recognized. CCK participates in the mediation of satiety; it interacts with dopamine and may modulate psychosis; it interacts with opiate systems and may be an "anti-analgesic": and it appears to play a role in the mediation of anxiety. Highly specific, CCK-B receptor antagonists have reached clinical trials and have potential clinical utility as anxiolytics, antipsychotics, anti-anorexics, or analgesics. There are grounds for excitement, but many obstacles remain to be overcome and clinical potential may not be fulfilled. However, we must not allow clinical disappointments to slow the accelerating pace of scientific progress in CCK research. Regardless of clinical payoffs, the CCK receptor is clearly of great importance to human CNS functioning and deserves ongoing scientific attention." [Abstract]

Bourin M, Malinge M, Vasar E, Bradwejn J.
Two faces of cholecystokinin: anxiety and schizophrenia.
Fundam Clin Pharmacol 1996;10(2):116-26
"It has been suggested that cholecystokinin (CCK), a gut-brain peptide found in high concentrations in the mammalian brain, might be implicated in the neurobiology of anxiety and panic disorder. The administration of CCK tetrapeptide induced panic attacks analogous to spontaneous ones in patients suffering from panic disorder and to a lesser degree in healthy volunteers. In animal models of anxiety, the pretreatment with CCK agonists and antagonists produced, respectively, anxiogenic- and anxiolytic-like action on the exploratory paradigms. On the other hand, CCK could also play a role in the pathophysiology of schizophrenia. The administration of CCK agonists (caerulein, CCK-8s) to rodents results in behavioural effects analogous to those of antipsychotic drugs. However, CCK agonists lack any activity in rodent behavioural models to reveal antipsychotic drugs. A significant reduction of CCK concentration and CCK receptors has been shown in cortical and limbic structures of patients suffering from schizophrenia. Nevertheless, administration of CCK agonists to these patients does not effect their symptoms. Two major conclusions should be drawn: first, CCK is involved in the neurobiology of anxiety; second, changes in the CCK system in schizophrenia could be linked to a cortical neurodegeneration related to this disease." [Abstract]

Abelson JL, Young EA.
Hypothalamic-pituitary adrenal response to cholecystokinin-B receptor agonism is resistant to cortisol feedback inhibition.
Psychoneuroendocrinology 2003 Feb;28(2):169-80
"Intravenous injection of the cholecystokinin (CCK)-B receptor agonist, pentagastrin, produces robust, dose-dependent release of adrenocorticotropin (ACTH) and cortisol, supporting the hypothesis that CCK-B agonists pharmacologically activate the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism of activation and its physiological relevance remain uncertain. Preliminary data suggest that the ACTH response to pentagastrin may be differentiated from the response to exogenous corticotropin releasing hormone (CRH) by its relative resistance to cortisol feedback inhibition. To more directly test the relationship between cortisol levels and ACTH response to pentagastrin, this study examined responses to pentagastrin (a) during a peak (8 a.m.) and a nadir (4 p.m.) period of endogenous cortisol secretion and (b) when cortisol levels were artificially reduced to low levels by administration of metyrapone. ACTH responses to pentagastrin were identical in the morning and afternoon, despite substantial differences in basal cortisol levels. Suppression of cortisol with metyrapone had little impact on ACTH response to pentagastrin. These data support the hypothesis that CCK-B receptor mediated activation of the HPA axis is relatively resistant to cortisol feedback inhibition. This differentiates it from CRH-mediated activation and raises the possibility that CCK could contribute to acute activation of the HPA axis even in the face of elevated basal cortisol levels, such as those seen in chronic stress or some psychiatric disorders." [Abstract]

Hernandez-Gomez AM, Aguilar-Roblero R, Perez De La Mora M.
Role of cholecystokinin-A and cholecystokinin-B receptors in anxiety.
Amino Acids 2002;23(1-3):283-90
"The aim of this work was to study whether CCKA receptors are also involved in the modulation of anxiety. Anxiogenic effects were observed in the elevated plus maze in rats when pure CCKB receptor agonists (CCK-4 and CCK-8 non-sulfated) or CCK-8S, a CCKB/CCKA agonist, were injected into the lateral ventricle. In contrast, CCK-33, a CCKA agonist or CCK-(1-21) and CCK-(26-29) were ineffective. Furthermore, the anxiogenic effects of CCK-8S were prevented by blocking CCKB but not CCKA receptors. Finally, CCK-33 injected into the postero-medial nucleus accumbens failed to affect the anxiety level of the rats. These results indicate that CCKA receptors are not involved in anxiety, as measured by the paradigms used in this work." [Abstract]

Izumi T, Inoue T, Tsuchiya K, Hashimoto S, Ohmori T, Koyama T.
Effect of the selective CCKB receptor antagonist LY288513 on conditioned fear stress in rats.
Eur J Pharmacol 1996 Apr 4;300(1-2):25-31
"In order to investigate the involvement of cholecystokinin (CCK) in the regulation of anxiety, the effect of the selective non-peptide CCKB receptor antagonist LY288513 ((4S, 5R)-N-(4-bromophenyl)-3-oxo-4,5-diphenyl-1-1-pyrazolidinecarboxamide+ ++) on freezing behavior induced by conditioned fear stress was examined using a time-sampling procedure. Rats were individually subjected to 5 min of inescapable electric footshock in a shock chamber. Twenty-four hours after the footshock, the rats were again placed in the shock chamber and observed for 5 min without shocks: this procedure is termed conditioned fear stress. Subcutaneous administration of LY288513 30 min before footshock (0.3 mg/kg) and 30 min before conditioned fear stress (0.03 mg/kg) reduced conditioned freezing. This indicates that LY288513 blocked both the acquisition and expression of conditioned fear. The relatively selective non-peptide CCKA receptor antagonist, lorglumide (D, L-4-(3,4-dichlorobenzoylamino)-5-(diphentylamino)-5-oxo-pent anoic acid), blocked the expression of conditioned fear, though only at a high dose (1.0 mg/kg). The peripheral non-peptide CCKA/B receptor antagonist, loxiglumide (D, L-4-(3,4-dichlorobenzoylamino)-5- (N-3-methoxypropyl-pentylamino)-5-oxo-pentanoic acid), failed to do so. These results suggest that brain CCKB receptors are involved in the regulation of anxiety." [Abstract]

Kellner M, Yassouridis A, Hua Y, Wendrich M, Naber D, Wiedemann K.
Trait dissociation affects the behavioral response to cholecystokinin tetrapeptide in healthy man.
Psychiatry Res 2002 Aug 5;111(1):93-6
"Trait dissociation might influence the response to panicogens in normal controls. The behavioral effects of 25 microg of cholecystokinin tetrapeptide (CCK-4) were studied in 18 healthy men, nine each with high or low trait dissociation. Subjects with high trait dissociation showed a significantly lower increase of acute dissociative, anxiety and panic symptoms compared with subjects with low trait dissociation. Trait dissociation should be assessed in further behavioral challenge studies as a potentially important covariate" [Abstract]

Katzman MA, Duffin J, Shlik J, Bradwejn J.
The ventilatory response to cholecystokinin tetrapeptide in healthy volunteers.
Neuropsychopharmacology 2002 Jun;26(6):824-31
"We conclude that CCK-4 does not act to induce panic by altering the central (CO(2) sensitive) chemoreceptor." [Abstract]

Danilova RA, Rud'ko OI, Korotkova TM, Obukhova MF, Ashmarin IP.
The effects of immunization against cholecystokinin fragment 30-33 in the behavior of white rats.
Neurosci Behav Physiol 2002 Mar-Apr;32(2):189-94
"Active immunization of white rats with cholecystokinin-4 covalently linked to the antigen carrier BSA evoked long-lasting changes in the rats' behavior, which were in the opposite direction to the anxiogenic effects of cholecystokinin-4 itself, showing that immunization had anxiolytic effects. Immunoenzyme analysis demonstrated the presence of antibodies to cholecystokinin-4 in the serum of immunized rats. These data are interesting from the point of view of correcting pathological anxiety and fear states by inverse immunoregulation." [Abstract]

Zwanzger P, Eser D, Aicher S, Schule C, Baghai TC, Padberg F, Ella R, Moller HJ, Rupprecht R.
Effects of alprazolam on cholecystokinin-tetrapeptide-induced panic and hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study.
Neuropsychopharmacology. 2003 May;28(5):979-84. Epub 2003 Mar 26.
"Cholecystokinin-tetrapeptide (CCK-4) induces panic attacks both in patients with panic disorder (PD) and healthy volunteers. It has been shown that panic elicited by CCK-4 is improved after treatment with antidepressants. Moreover, a reduction of CCK-4-induced panic has also been demonstrated after treatment with lorazepam in single subjects and after selective GABAergic treatment with vigabatrin. Although benzodiazepines are widely used as anxiolytics, no controlled study on the effects of benzodiazepines on CCK-4-induced panic symptoms is available so far. Therefore, we investigated the effects of alprazolam and placebo on CCK-4-induced panic symptoms in a double-blind, placebo-controlled study. A total of 30 healthy subjects were challenged with 50 microg CCK-4. Out of these 30 subjects, 26 showed a marked panic response to CCK-4. Subjects were rechallenged after a 7-day interval and treated with 1 mg alprazolam or placebo 1 h prior to the second CCK-4 challenge. Panic was assessed using the acute panic inventory (API) and a DSM-IV-derived panic symptom scale (PSS). Moreover, the number of reported symptoms and self-rated anxiety and arousal were recorded. We found a significant reduction of the API and PSS scores and of the number of reported symptoms compared to placebo. Moreover, compared to placebo the CCK-4-induced ACTH and cortisol release were significantly attenuated during the CCK-4 challenge after alprazolam treatment. However, also placebo treatment reduced CCK-4-induced anxiety and HPA-axis activation to a certain extent. In conclusion, our data show that alprazolam reduces CCK-4-induced panic, which supports the hypothesis of a possible interaction between the GABA and the CCK system." [Abstract]

Zwanzger P, Baghai TC, Schuele C, Strohle A, Padberg F, Kathmann N, Schwarz M, Moller HJ, Rupprecht R.
Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers.
Neuropsychopharmacology 2001 Nov;25(5):699-703 [Abstract]

Zwanzger P, Eser D, Padberg F, Baghai TC, Schule C, Rotzer F, Ella R, Moller HJ, Rupprecht R.
Effects of tiagabine on cholecystokinin-tetrapeptide (CCK-4)-induced anxiety in healthy volunteers.
Depress Anxiety. 2003;18(3):140-3. [Abstract]

Raud S, Runkorg K, Veraksits A, Reimets A, Nelovkov A, Abramov U, Matsui T, Bourin M, Volke V, Koks S, Vasar E.
Targeted mutation of CCK2 receptor gene modifies the behavioural effects of diazepam in female mice.
Psychopharmacology (Berl). 2003 Aug;168(4):417-25. Epub 2003 Apr 23.
"RATIONALE: Evidence suggests that GABA and CCK have opposite roles in the regulation of anxiety. OBJECTIVE: The aim of the present work was to study diazepam-induced anxiolytic-like action and impairment of motor co-ordination, and the parameters of benzodiazepine receptors in mice lacking CCK2 receptors. METHODS: The action of diazepam (0.5-3 mg/kg i.p.) was studied in the elevated plus-maze model of anxiety and rotarod test using mice lacking CCK2 receptors. The parameters of benzodiazepine receptors were analysed using [3H]-flunitrazepam binding. RESULTS: In the plus-maze test, the exploratory activity of the homozygous (-/-) mice was significantly higher compared to their wild-type (+/+) littermates. However, the wild-type (+/+) mice displayed higher sensitivity to the anxiolytic-like action of diazepam. Even the lowest dose of diazepam (0.5 mg/kg) induced a significant increase of open arm entries in the wild-type (+/+) mice. A similar effect in the homozygous (-/-) mice was established after the administration of diazepam 1 mg/kg. The highest dose of diazepam (3 mg/kg) caused a prominent anxiolytic-like effect in the wild-type (+/+) mice, whereas in the homozygous (-/-) animals suppression of locomotor activity was evident. The performance of the homozygous (-/-) mice in the rotarod test did not differ from that of the wild-type (+/+) littermates. However, a difference between the wild-type (+/+) and homozygous (-/-) animals became evident after treatment with diazepam. Diazepam (0.5 and 3 mg/kg) induced significantly stronger impairment of motor co-ordination in the homozygous (-/-) mice compared to their wild-type (+/+) littermates. The density of benzodiazepine binding sites was increased in the cerebellum, but not in the cerebral cortex and hippocampus, of the homozygous (-/-) mice. CONCLUSIONS: Female mice lacking CCK2 receptors are less anxious than their wild-type (+/+) littermates. The reduced anxiety in homozygous (-/-) mice probably explains why the administration of a higher dose of diazepam is necessary to induce an anxiolytic-like action in these animals. The highest dose of diazepam (3 mg/kg) induced significantly stronger suppression of locomotor activity and impairment of motor co-ordination in the homozygous (-/-) mice compared to the wild-type (+/+) littermates. The increase in the action of diazepam is probably related to the elevated density of benzodiazepine receptors in the cerebellum of homozygous (-/-) mice. The present study seems to be in favour of increased tone of the GABAergic system in mice without CCK2 receptors." [Abstract]

Strohle A, Romeo E, di Michele F, Pasini A, Hermann B, Gajewsky G, Holsboer F, Rupprecht R.
Induced panic attacks shift gamma-aminobutyric acid type A receptor modulatory neuroactive steroid composition in patients with panic disorder: preliminary results.
Arch Gen Psychiatry. 2003 Feb;60(2):161-8.
"BACKGROUND: Certain metabolites of progesterone such as 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP; allopregnanolone) and 3alpha,5beta-THP (pregnanolone) are potent, positive allosteric modulators of gamma-aminobutyric acid type A receptors. Although animal studies suggest anxiolytic properties of these endogenous modulators of central nervous excitability, no clinical data indicate whether they are also involved in the pathophysiology of anxiety disorders and panic attacks. METHODS: We quantified the concentrations of 3alpha,5alpha-THP, 3alpha,5beta-THP, the isomer 3beta,5alpha-THP, and their precursors in the plasma of 10 patients with panic disorder and matched control subjects during panic attacks induced by means of sodium lactate and cholecystokinin tetrapeptide administration, using a highly sensitive gas chromatography-mass spectrometry analysis. RESULTS: Panic attacks induced by sodium lactate and cholecystokinin tetrapeptide in patients with panic disorder were accompanied by pronounced decreases in the concentrations of 3alpha,5alpha-THP and 3alpha,5beta-THP and a concomitant increase in the concentrations of the functional antagonistic isomer 3beta,5alpha-THP, findings that are compatible with a decreased gamma-aminobutyric acid-ergic tone. No changes in neuroactive steroid concentrations were observed after placebo administration in patients with panic disorder or after placebo, sodium lactate, or cholecystokinin tetrapeptide administration in controls. CONCLUSIONS: The association between changes in plasma neuroactive steroid concentrations and experimentally induced panic attacks and the well-documented pharmacological properties of these compounds as gamma-aminobutyric acid type A receptor modulators suggest that neuroactive steroids may play a role in the pathophysiology of panic attacks in patients with panic disorder." [Abstract]

Siniscalchi A, Rodi D, Cavallini S, Marino S, Ferraro L, Beani L, Bianchi C.
Effects of cholecystokinin tetrapeptide (CCK(4)) and of anxiolytic drugs on GABA outflow from the cerebral cortex of freely moving rats.
Neurochem Int. 2003 Jan;42(1):87-92.
"The effect of cholecystokinin tetrapeptide (CCK(4)) and of different anxiolytic drugs on GABA outflow from the cerebral cortex was investigated in freely moving rats, by using the epidural cup technique. CCK(4) (3-30 microg/kg, i.p.) increased GABA outflow and induced objective signs of anxiety. These neurochemical and behavioral responses were prevented by the CCK(B) antagonist GV150013 at 0.1 microg/kg (i.p.). At higher doses (up to 30 microg/kg) this compound per se reduced GABA release and caused sedation, suggesting the presence of a CCKergic positive tonic modulation on GABA interneurons. Similarly the GABA(A) receptors modulator, diazepam (2mg/kg, i.p.) and the 5-HT(1A) agonist buspirone (3mg/kg, i.p.) reduced GABA outflow and caused the expected behavioral effects (reduced muscle tone, mild 5-HT syndrome) which were prevented by the respective, selective antagonists, flumazenil (1mg/kg, i.p.) and NAN-190 (3mg/kg, i.p.). These findings support the idea that GV150013, diazepam and buspirone inhibit GABAergic cortical activity, through the respective receptors. This neurochemical effect may represent the end-effect of various anxiolytic compounds affecting the cortical circuitry." [Abstract]

Dauge V, Sebret A, Beslot F, Matsui T, Roques BP.
Behavioral profile of CCK2 receptor-deficient mice.
Neuropsychopharmacology 2001 Nov;25(5):690-8
"CCK2 receptor-deficient mice were used to investigate in vivo the role of this receptor in behavior. Mutant mice showed a neuromuscular impairment in the traction and rotarod tests but not in the chimney test. Brain cholecystokinin has been shown to participate in stress-related behaviors. However, CCK2 receptor-deficient mice did not show behavioral modifications compared to wild-type mice in the elevated plus maze and in the motility conditioned suppression test, indicating that compensatory mechanisms very likely occur following CCK2 receptor invalidation. On the other hand, a hyperlocomotor activity was observed in actimeter which can be related to an impairment in environmental habituation. Finally, CCK2 receptor-deficient mice showed an impairment of performance in the spontaneous alternation behavior as expected from the opposite effects evoked by CCK2 agonists, supporting the physiological role of CCK2 receptors in attention and/or memory processes. This result is reinforced by the defects observed in these functions after the administration of CCK2 antagonists." [Abstract]

Siniscalchi A, Rodi D, Cavallini S, Marino S, Beani L, Bianchi C.
Effects of cholecystokinin tetrapeptide (CCK(4)) and anxiolytic drugs on the electrically evoked [(3)H]5-hydroxytryptamine outflow from rat cortical slices.
Brain Res 2001 Dec 13;922(1):104-11
"The outflow of [(3)H]5-hydroxytryptamine ([(3)H]5-HT) from electrically stimulated rat cortical slices was measured to ascertain the modulatory role of endogenous cholecystokinin (CCK) on the amine outflow and to test the hypothesis that different anxiolytic compounds inhibit 5-HT secretion. The [(3)H]5-HT outflow evoked at 10 Hz was increased up to +30% by CCK(4) 300-1000 nM, the effect being prevented by the CCK(B) receptor antagonist GV 150013, 3 nM. The limited sensitivity to CCK(4) seemed to depend on 5-HT auto-receptor feedback because pre-treatment with 100 nM methiothepin enhanced the [(3)H]5-HT outflow and lowered the CCK(4) threshold concentration from 300 to 30 nM. In addition, pre-treatment with 1 microM bacitracin to inhibit CCK metabolism increased [(3)H]5-HT efflux. This effect was concentration-dependently counteracted by GV150013 suggesting the presence of an endogenous CCK positive modulation. GV150013 30 nM, the 5-HT(1A) partial agonist buspirone 300 nM and the GABA(A) receptor modulator diazepam 10 nM, known to have anxiolytic properties, all significantly reduced the [(3)H] amine outflow from cortical slices by about 20%. This inhibition depended on their interaction with their respective receptors, which seemed to restrain the activity of functionally interconnected glutamatergic interneurones. In fact, APV (50 microM) and NBQX (10 microM) prevented the effect of the anxiolytic compounds. Thus, anxiolytic drugs with different receptor targets can reduce 5-HT outflow by dampening the glutamatergic signal, and in turn, the secretory process of the serotonergic nerve ending." [Abstract]

Buyse M, Bado A, Dauge V.
Leptin decreases feeding and exploratory behaviour via interactions with CCK(1) receptors in the rat.
Neuropharmacology 2001 May;40(6):818-25
"We assessed the effects of peripheral leptin on anxiety and exploratory behaviour in the elevated plus-maze and in the four-hole box or Y-maze tests, in rats fed 80% of normal daily food intake and rats fed ad libitum. In the Y-maze test, i.p. injection of 0.4 or 1 mg/kg leptin into rationed rats significantly decreased the percentage of spontaneous alternation behaviour and increased the number of visits. In the elevated plus-maze test, rationed rats spent significantly more time in the open arms (aversive part of the maze) than did rats fed ad libitum. This difference in behaviour was abolished by injecting 0.4 mg/kg leptin. In the four-hole box test, i.p. administration of 1 mg/kg leptin significantly reduced the duration and number of hole visits in rationed and ad libitum fed rats. As with leptin inhibition of food intake, these behavioural changes caused by leptin were prevented by a CCK(1) receptor antagonist (L364,718), at a dose that had no effect by itself. Finally, a 20-min stress that increased corticosterone and ACTH levels had no effect on circulating leptin levels and on the leptin content of epididymal fat tissue, stomach and brain. Thus, leptin induces hypoexploration and decreases spontaneous alternation in rats and these effects are partly dependent on nutritional status. These results also suggest that the CCK system may be involved in the induction of these behavioural changes in rats by leptin, via the CCK(1) receptor." [Abstract]

Abelson JL, Le Melledo J, Bichet DG.
Dose response of arginine vasopressin to the CCK-B agonist pentagastrin.
Neuropsychopharmacology 2001 Feb;24(2):161-9
"Cholecystokinin (CCK) is a peptide neurotransmitter that modulates hypothalamic-pituitary-adrenal (HPA) axis activity and may be involved in fear or anxiety states. Arginine vasopressin (AVP) also modulates HPA axis activity and may play a role in fear conditioning. Few human studies have examined interactions between CCK and AVP systems. To explore relationships between CCK-B receptor activation, the HPA axis response, and AVP release, a dose-response study using the CCK-B receptor agonist pentagastrin was conducted. Adrenocorticotropin (ACTH) and cortisol results have been previously reported and AVP data is presented here. Thirty-five healthy subjects were randomly assigned to receive placebo, or 0.2, 0.4, 0.6, or 0.8 microg/kg doses of pentagastrin. AVP release appeared to increase with increasing doses of the CCK-B agonist. However, this may have been due to a greater percentage of subjects releasing AVP in the higher dose groups, rather than a direct effect of dose on magnitude of response. AVP and ACTH responses were correlated, but AVP response alone could not account for the magnitude of the ACTH response. AVP release was significantly correlated with anxiety symptom responses. These findings suggest a possible role for the CCK-B receptor in AVP release, which may be at least partially separate from its role in modulation of the HPA axis. Further work is needed to determine whether these are physiologically meaningful interactions and to determine their functional implications." [Abstract]

Singewald N, Sharp T.
Neuroanatomical targets of anxiogenic drugs in the hindbrain as revealed by Fos immunocytochemistry.
Neuroscience 2000;98(4):759-70
"It is speculated that specific hindbrain transmitter pathways centred on the periaqueductal gray and locus coeruleus are an important integrative neural substrate for the expression of anxiety and the somatic symptoms and cardiovascular changes that accompany severe anxiety states, such as in panic disorder. Here we investigated the effects of various drugs, known to induce panic in humans and to be anxiogenic in animals, on Fos expression in the periaqueductal gray, locus coeruleus and other parts of the rat hindbrain. The drugs tested were the benozodiazepine inverse agonist FG-7142, the alpha(2)-adrenoceptor antagonist yohimbine, the non-selective 5-hydroxytryptamine(2C) receptor agonist m-chlorophenyl piperazine, the adenosine antagonist caffeine and the cholecystokinin analogue BOC-CCK(4). A clear-cut finding was that administration of each anxiogenic drug caused a striking region-specific pattern of Fos expression within the hindbrain. In particular, the drugs commonly increased Fos-like immunoreactivity in the periaqueductal gray and locus coeruleus. Increased Fos expression in the periaqueductal gray was specific to the rostral dorsolateral and caudal ventrolateral regions. All the anxiogenic drugs also increased Fos-like immunoreactivity in the lateral parabrachial nucleus and nucleus of the solitary tract and all but one (BOC-CCK(4)) increased Fos in the dorsal raphe nucleus. Rats habituated to the test environment and injected with saline vehicle displayed little or no Fos-like immunoreactivity in the hindbrain areas investigated.In summary, each of the anxiogenic drugs tested (FG-7142, yohimbine, m-chlorophenyl piperazine, caffeine and BOC-CCK(4)) increased Fos expression in a restricted number of hindbrain regions, including the periaqueductal gray and locus coeruleus. Previous Fos studies have found that these same regions are activated by various fearful environmental stimuli. Therefore, a specific set of hindbrain circuits may be commonly involved in the processing of anxiety-related information evoked by pharmacological and environmental manipulation. The present findings also raise the possibility that measurement of the effect of anxiogenic drugs on Fos expression might be a useful way to model hindbrain pathways activated by anxiety and possibly panic." [Abstract]

Koks S, Mannisto PT, Bourin M, Shlik J, Vasar V, Vasar E.
Cholecystokinin-induced anxiety in rats: relevance of pre-experimental stress and seasonal variations.
J Psychiatry Neurosci 2000 Jan;25(1):33-42
"OBJECTIVE: To examine the influence of pre-experimental stress on the anxiogenic-like action of caerulein, an agonist of cholecystokinin (CCK) receptors. Differences in the anxiety levels of rats in summer and winter, and the role of CCK in these behavioural alterations, were also examined. DESIGN: Prospective animal study. INTERVENTIONS: Male Wistar rats were injected with the CCK agonist caerulein, or the CCK antagonists L-365,260 or devazepide, after being exposed to pre-experimental stress (handling and isolation). OUTCOME MEASURES: Performance in the plus-maze model of anxiety; serum levels of prolactin, thyrotropin and growth hormone; brain density and affinity of dopamine D2, serotonin 5-HT2 and CCK receptors. RESULTS: Caerulein (5 micrograms/kg, subcutaneous injection) caused the strongest action in animals brought to the experimental room immediately before the experiment and kept in isolation after the administration of caerulein. Caerulein did not cause any reduction of exploratory activity in rats made familiar with the experimental room and kept in the home-cage after the injection of the CCK agonist. The anti-exploratory action of caerulein in stressed rats was reversed by the CCK antagonist L-365,260 (100 micrograms/kg, intraperitoneal injection), demonstrating the involvement of the CCKB receptor subtype. In addition, seasonal fluctuations occur in the exploratory activity of rats; such activity was much lower in July than in November. The rats displaying the reduced exploratory activity had an increased number of CCK receptors in the frontal cortex and hippocampus. Simultaneously, the density of serotonin 5-HT2 receptors in the frontal cortex, but not that of dopamine D2 receptors in the striatum, was elevated. The blood level of growth hormone was also higher in July. CONCLUSIONS: The anti-exploratory action of caerulein appears to be dependent on the pre-experimental stress of rats. Moreover, the seasonal variations of exploratory behaviour of rats are evident in the plus-maze model of anxiety. The reduced exploratory activity in summer appears to be related to the elevated density of CCK and 5-HT2 receptors in the brain." [Abstract]

Kellner M, Wiedemann K, Yassouridis A, Levengood R, Guo LS, Holsboer F, Yehuda R.
Behavioral and endocrine response to cholecystokinin tetrapeptide in patients with posttraumatic stress disorder.
Biol Psychiatry 2000 Jan 15;47(2):107-11
"BACKGROUND: Given the relationship between posttraumatic stress disorder (PTSD) and panic, it was of interest to examine whether panic provoking agents affect PTSD symptoms. We therefore investigated the behavioral and endocrine response of PTSD patients to the panicogen cholecystokinin tetrapeptide (CCK-4). METHODS: Eight patients with PTSD (DSM-IV) received 50 micrograms CCK-4 intravenously in a placebo-controlled, double-blind balanced design. Provocation of panic, anxiety, and flashbacks was assessed. Plasma adrenocorticotropin (ACTH) and cortisol levels after CCK-4 were measured and compared to healthy subjects matched for age, gender, and provoked symptoms. RESULTS: Despite significant effects of CCK-4 on anxiety and panic symptoms, no significant provocation of flashbacks emerged. CCK-4-induced panic symptoms showed an inverse correlation to trait dissociation. The ACTH response after CCK-4 was significantly lower in PTSD patients than in controls. Cortisol was similarly increased in both groups after CCK-4, but PTSD patients showed a more rapid decrease of stimulated cortisol concentrations. CONCLUSIONS: Panic symptoms or heightened anxiety are not necessarily conditioned stimuli for the provocation of posttraumatic flashbacks. Further studies in PTSD with different panicogens should be controlled for the potential interference of trait dissociation. Our hormone data show further evidence for a corticotropin-releasing hormone (CRH) overdrive and enhanced negative glucocorticoid feedback in PTSD patients." [Abstract]

Koks S, Soosaar A, Voikar V, Bourin M, Vasar E.
BOC-CCK-4, CCK(B)receptor agonist, antagonizes anxiolytic-like action of morphine in elevated plus-maze.
Neuropeptides 1999 Feb;33(1):63-9
"This study investigated a role of cholecystokinin (CCK) in the anxiolytic-like action of morphine, an agonist of mu-opioid receptors, in the rat plus-maze model of anxiety. The acute administration of morphine (1 mg/kg) induced a significant increase of exploratory activity in the plus-maze, but did not affect the locomotor activity in the motility test. The higher dose of morphine (2.5 mg/kg) tended to decrease the locomotor activity and, therefore, did not cause the anxiolytic-like action in the plus-maze. The other drugs (naloxone, BOC-CCK-4, L-365,260) and their combinations with morphine (0.5-1 mg/kg) did not affect the locomotor activity of rats. The opioid antagonist naloxone itself (0.5 mg/kg) did not change the exploratory activity in the plus-maze, but potently antagonized the anxiolytic-like action of morphine (1 mg/kg). An agonist of CCK(B)receptors BOC-CCK-4 (1-50 microgram/kg) induced a dose-dependent anxiogenic-like action in the plus-maze. Nevertheless, only one dose of BOC-CCK-4 (10 microgram/kg) completely reversed the action of morphine. Also, one dose of CCK(B)receptor antagonist L-365,260 (10 microgram/kg) was effective to modify the behaviour of rats in the elevated plus-maze. Namely, this dose of L-365,260 increased the ratio between open and total arm entries, a behavioural measure believed to reflect the anxiolytic-like action in the elevated plus-maze. The combination of L-365,260 (100 microgram/kg) with the sub-effective dose of morphine (0.5 mg/kg) caused the anxiolytic-like action in the plus-maze not seen if the drugs were given alone. In conclusion, morphine induces a potent anxiolytic-like action in the elevated plus-maze and CCK is acting as an endogenous antagonist of this effect of morphine." [Abstract]

Geracioti TD Jr, Ekhator NN, Nicholson WE, Arndt S, Loosen PT, Orth DN.
Intra- and inter-individual correlations between cholecystokinin and corticotropin-releasing hormone concentrations in human cerebrospinal fluid.
Depress Anxiety 1999;10(2):77-80
"Despite strong evidence of a physiologic relationship between cholecystokinin (CCK) and corticotropin-releasing hormone (CRH) in the rat central nervous system (CNS), evidence of such a relationship between the two hormones in the human CNS is lacking. A post hoc analysis of serial concentrations of immunoreactive CCK and CRH, obtained every ten minutes from CSF continuously collected over six hours, was performed. A total of 30 subjects were studied: 15 normal volunteers, 10 patients with major depression, and 5 recently-abstinent, alcohol-dependent patients. Overall, we observed an average intra-subject correlation of +.273 (P < 0.001) between CSF CRH and CCK. Inter-subject correlations between mean CSF levels of CRH and CCK were +.948 (P = 0.0001) and +.959 (P = 0.005) in the depressed and abstinent alcoholic patients, respectively. These inter-individual correlations were significantly greater than that seen within the group of normal volunteers (r = +.318, n.s.). The present data suggest that interactions between CCK and CRH are significant in the human CNS, particularly perhaps in depressed and alcoholic patients, and that CSF samples may be used to assess elements of the relationship between these hormones." [Abstract]

Okubo T, Harada S, Higuchi S, Matsushita S.
Genetic association between alcohol withdrawal symptoms and polymorphism of CCK gene promoter.
Alcohol Clin Exp Res 1999 Apr;23(4 Suppl):11S-12S
"In the central nervous system, cholecystokinin (CCK) is an important neurotransmitter that gives the influences on firings, anxiety, notiception, and dopamine-related behavior. CCK co-exists in the dopaminergic neurons, interacting with dopamine. In this study, we examined the genetic variant -45 C to T substitution of the CCK gene promoter region among 195 healthy Japanese and 174 patients with alcohol withdrawal syndrome (52 delirium tremens, 39 hallucinosis, 20 seizures, and 92 lack of these symptoms) by using polymerase chain reaction-based single-strand conformational polymorphism analysis. Patients with delirium tremens showed a significantly higher frequency of the variant, compared with the controls (chi2 = 4.91, p < 0.03), but patients with other symptoms showed no difference. These data suggested that the individuals possessing allelic mutation (-45T) in the promoter region of the CCK gene might be susceptible to delirium tremens caused by alcohol abuse." [Abstract]

Holmes BB, Rady JJ, Smith DJ, Fujimoto JM.
Supraspinal neurotensin-induced antianalgesia in mice is mediated by spinal cholecystokinin.
Jpn J Pharmacol 1999 Feb;79(2):141-9
"Intracerebral injection of neurotensin into specific brain loci in rats produces hyperalgesia due to the release of cholecystokinin (CCK) in the spinal cord. The present purpose was to show in another species that neurotensin can antagonize the antinociceptive action of morphine through the spinal CCK mechanism in mice. Neurotensin given intracerebroventricularly (i.c.v.) at doses higher than 100 ng produced antinociception in the tail flick test. However, at lower doses between 1 pg to 25 ng, neurotensin antagonized the antinociceptive action of morphine given intrathecally (i.t.), thus demonstrating the antianalgesic activity of neurotensin. The rightward shift in the morphine dose-response curve produced by i.c.v. neurotensin was eliminated by an i.t. pretreatment with CCK8 antibody (5 microl of antiserum solution diluted 1:1000). I.t. administration of lorglumide, a CCK(A)-receptor antagonist (10-1000 ng), and PD135,158, a CCK(B)-receptor antagonist (250-500 ng), also eliminated the antianalgesic action of neurotensin. Thus, the mechanism of the antianalgesic action of neurotensin given i.c.v. involved spinal CCK. This mode of action is similar to that for the antianalgesic action of supraspinal pentobarbital which also involves spinal CCK." [Abstract]

Jerabek I, Boulenger JP, Bradwejn J, Lavallee YJ, Jolicoeur FB.
CCK4-induced panic in healthy subjects I: psychological and cardiovascular effects.
Eur Neuropsychopharmacol 1999 Jan;9(1-2):149-55
"Sixteen healthy subjects participated in a crossover, double blind, and placebo-controlled study, designed to assess simultaneously the psychological and cardiovascular effects of cholecystokinin tetrapeptide (CCK4). Following an i.v. injection of 25 microg of CCK4, 44 percent of subjects experienced symptoms that fulfilled the DSM-IV criteria for a panic attack while no one panicked with placebo. CCK4 induced a significantly greater number and higher intensity of panic-like symptoms than placebo. A significant increase in state anxiety was observed in the period after CCK4 injection; this increase was significantly larger than the non-specific anxious reaction to placebo. CCK4 also affected cardiovascular signs. Both heart rate and mean blood pressure significantly increased after administration of CCK4. Again, these increases were significantly higher than those seen after placebo injection. We conclude that, in healthy subjects, CCK4 induces panic-like reaction characterized by a number of somatic, cognitive and emotional symptoms, which are accompanied by increases in heart rate and blood pressure." [Abstract]

Javanmard M, Shlik J, Kennedy SH, Vaccarino FJ, Houle S, Bradwejn J.
Neuroanatomic correlates of CCK-4-induced panic attacks in healthy humans: a comparison of two time points.
Biol Psychiatry 1999 Apr 1;45(7):872-82
"BACKGROUND: Several functional imaging studies have demonstrated increases of brain activity in the temporofrontal, cingulate, and claustrum regions during a pharmacologically induced panic attack when scanning was done at a single point in time. However, no study has evaluated changes in brain activity at two time points during a panic attack. We hypothesized that in response to a single bolus injection of the panicogen cholecystokinin-4 (CCK-4) in healthy volunteers, changes in regional cerebral blood flow (rCBF) might be different if scanning were done at two different time points. METHODS: To test this hypothesis, we conducted a single-blind study, using positron emission tomography (PET). To determine the time effect of panic attack on brain activity, we performed either early scan or late scan covering the first or the second minute after CCK-4 bolus injection, respectively. The PET images were analyzed by statistical parametric mapping (SPM) followed by region of interest (ROI) analysis. RESULTS: The results showed significant differences between the early and the late scan. The early effects of CCK-4 are accompanied by increases in rCBF in the hypothalamic region, whereas the late scan showed an increase in rCBF in the claustrum-insular region. Reductions in rCBF were observed for both time groups in the medial frontal region. A separate scan for anticipatory anxiety demonstrated rCBF increases in the anterior cingulate region and decreases in the occipital regions. CONCLUSIONS: These results may support the hypothesis that changes in rCBF as a function of time during CCK-4-induced panic might correspond to a neurocircuitry involved in panic attacks." [Abstract]

Griebel G, Perrault G, Sanger DJ.
CCK receptor antagonists in animal models of anxiety: comparison between exploration tests, conflict procedures and a model based on defensive behaviours.
Behav Pharmacol 1997 Nov;8(6-7):549-60
"The present experiments compared the behavioural effects of one cholecystokininA (CCKA; lorglumide) and two CCKB (PD 135,158 and LY 288513) receptor antagonists in classical animal models of anxiety, including conflict tests (punished lever pressing and Vogel drinking tests in rats) and exploratory models (elevated plus-maze test in rats and light/dark choice test in mice), and a recently developed mouse defence test battery (MDTB) which has been validated for the screening of both anti-panic and classical anxiolytic (i.e. benzodiazepines) drugs. Diazepam was used as a positive control. Results showed that all three CCK receptor antagonists were inactive in both conflict tests. Furthermore, despite the incorporation of more ethologically-derived measures (i.e. risk assessment activities or directed exploration, or both) no effects were observed in the elevated plus-maze and in the light/dark tests. These profiles contrast with that of diazepam which displayed clear anxiolytic-like effects in these models. In the MDTB, the CCK receptor antagonists failed to modify parameters (i.e. risk assessment, defensive threat/attack and escape attempts), which have been shown to be particularly sensitive to drugs effective in the treatment of generalized anxiety. By contrast, the CCKB receptor antagnoists PD 135,158 (0.001-0.01, 1 mg/kg, i.p.) and LY 288513 (1 and 3 mg/kg, i.p.) significantly decreased avoidance distance when the rat was first placed in the test apparatus, an effect which is consistent with an anti-panic-like action. Overall, these findings support the idea that classical animal models of anxiety may not be suitable for evaluation of the behavioural effects of CCK receptor antagonists, whereas tests which may model certain aspects of human panic such as the MDTB appear to be more reliable tools when screening such compounds." [Abstract]

Dauge V, Lena I.
CCK in anxiety and cognitive processes.
Neurosci Biobehav Rev 1998 Oct;22(6):815-25
"Extensive studies were carried out on the involvement of the CCKergic system in anxiety-, panic- and stress-related behaviour. The stimulation of CCK-A or CCK-B receptors is implicated in the physical and psychological responses of CCK to stress. Furthermore, several selective CCK-B agonists produce anxiogenic-like effects, while CCK-B antagonists induce anxiolytic-like responses in several models of anxiety. However, BC264 a highly selective CCK-B agonist, does not produce anxiogenic-like effects but increases attention and/or memory. These effects are dependent on the dopaminergic systems. Together with biochemical data, this led to the hypothesis of the existence of two CCK-B binding sites, CCK-B1 and CCK-B2, which could correspond to different activation states of a single molecular entity. Investigations into CCK-B1 and CCK-B2 systems might be of critical interest, since only one site, CCK-B1, appears to be responsible for the effects of anxiety. Furthermore, the improvement of attention and/or memory processes by CCK, through CCK-B2 receptors, could offer a new perspective in the treatment of attention and/or memory disorders." [Abstract]

Acosta GB.
Administration of cholecystokinin sulphated octapeptide (CCK-8S) induces changes on rat amino acid tissue levels and on a behavioral test for anxiety.
Gen Pharmacol 1998 Oct;31(4):637-41
"1. The effect of the intraperitoneal administration of cholecystokinin sulphated octapeptide (CCK-8S) (10 nmol/kg i.p.) on endogenous levels of several amino acids in five areas of the rat brain was analyzed. The olfactory bulb, hypothalamus, hippocampus, cerebral frontal cortex, and corpus striatum were evaluated. In addition, the effects of CCK-8S and PD 135,158 (1 mg/kg), a selective CCK(B) antagonist, on the performance of rats submitted to a dark/light transition test were also studied. 2. Upon administration of CCK-8S, the concentration of glutamate was reduced (27%) in the olfactory bulb. The same was observed when the levels of glycine (31%) or alanine (43%) were determined. No significant effects were produced by CCK-8S on cortical and hypothalamic levels. In the hippocampus, the concentration of both glutamate (27%) and taurine (29%) were reduced, whereas the levels of GABA in the striatum (29%) were increased. 3. After a single injection of CCK-8S, the time spent by the rats in the illuminated site of the dark/light transition test box, was not changed. On the contrary, the administration of PD 135,158 increased the time spent in the lighted compartment. 4. These results show that systemic administration of CCK-8S produced regional specific changes in brain amino acids, without producing any significant behavioral modification in the rat exposed to a dark/light box. In contrast, the selective CCKB receptor antagonist, PD 135,158, induces anxiolytic-like action in an animal model of anxiety." [Abstract]

Wilson J, Watson WP, Little HJ.
CCK(B) antagonists protect against anxiety-related behaviour produced by ethanol withdrawal, measured using the elevated plus maze.
Psychopharmacology (Berl) 1998 May;137(2):120-31
"The effects of the CCK(B) antagonists, CAM1028 and CI988 and a CCK(A) antagonist, CAM1481, were studied on the anxiety-related behaviour produced by withdrawal from chronic ethanol treatment, using the elevated plus maze. Cessation of chronic ethanol administration produced a profile, in both mice and rats, consistent with increase in anxiety-related behaviour. In mice, SC administration of CAM1028 or CI988 reduced the decrease in the time spent on the open arms, the number of entries into these arms and the increases in the latencies to first open arm entry, after withdrawal from the ethanol treatment. The increases in stretched attend postures and head dips from the closed arms and the central square seen during the withdrawal phase, were also decreased by the CCK(B) antagonists, but the decreases in the number of rears and in general activity were unaffected. The doses of CAM1028 and CI988 tested were 0.1 and 1 mg/kg; for some of the withdrawal-induced changes in behaviour only the 1 mg/kg dose was effective. In contrast, the CCK(A) antagonist, CAM1481, at the same doses, had little effect on the anxiety-related behaviour produced by withdrawal from chronic ethanol treatment, although it did decrease the changes in the number of rears and the head dipping behaviour. In rats, the majority of the changes produced by withdrawal from chronic ethanol treatment were decreased by CAM1028 at 1 mg/kg, although the decreases in open arm entries, rearing behaviour and in overall activity were unaffected. CAM1028, CI988 and CAM1481 had no effects on the behaviour of control mice or rats in the plus-maze. The results show that CCK(B) antagonists were effective in decreasing the majority of the anxiogenic effects of withdrawal from chronic ethanol treatment." [Abstract]

Lofberg C, Agren H, Harro J, Oreland L.
Cholecystokinin in CSF from depressed patients: possible relations to severity of depression and suicidal behaviour.
Eur Neuropsychopharmacol 1998 May;8(2):153-7
"Levels of cholecystokinin (CCK) peptides were measured in the CSF from 105 patients suffering from major depressive disorders admitted to a research psychiatric ward for diagnostic evaluation, by a radioimmunoassay method using two different antibodies. Relations between CCK levels and parameters of depression, anxiety, and suicidal behaviour were investigated. Significant inverse correlations were found between CCK levels and certain depression and anxiety parameters. Patients who had made one or more suicide attempts tended to have higher CSF CCK levels than those who had not. No correlations were found between CSF CCK and 5-HIAA or HVA, or with plasma cortisol." [Abstract]

Bloom FE, Morales M.
The central 5-HT3 receptor in CNS disorders.
Neurochem Res 1998 May;23(5):653-9
"Among the characterized 5-HT receptors of the central nervous system, the type 3 receptor subtype (5-HT3R) is the only one known to be a ligand-gated ion channel. Its early pharmacological characterization and mapping by radioligand binding autoradiography suggested that this receptor may, among other actions, regulate dopamine release in the nigro-striatal pathway and reduce alcohol consumption in experimental animals while antagonists of this receptor have been reported to treat anxiety disorders. Following the cloning of this receptor in 1991, direct cellular localization was made possible by in situ hybridization and immunohistochemical analysis. Here we summarize our recent efforts showing that 5-HT3R-expressing neurons are mainly GABA containing cells in the rat neocortex, olfactory cortex, hippocampus, and amygdala which also often contain cholecystokinin (CCK) immunoreactivity. These results provide a means to unify some of the initial pharmacological observations." [Abstract]

Nevo I, Becker C, Hamon M, Benoliel JJ.
Stress- and yohimbine-induced release of cholecystokinin in the frontal cortex of the freely moving rat: prevention by diazepam but not ondansetron.
J Neurochem 1996 May;66(5):2041-9
"The in vivo release of cholecystokinin (CCK)-like material (CCKLM) was measured in the frontal cortex of freely moving rats using the microdialysis technique combined with a sensitive radioimmunoassay. Local perfusion of K+ (100 mM)-enriched artificial CSF resulted in a 10-fold increase in CCKLM outflow, as compared with that occurring under basal resting (K+ = 3.0 mM) conditions, and this effect could be completely prevented by removal of Ca2+ in the perfusing fluid. Chromatographic analyses demonstrated that CCK-8S contributed to 70% of CCKLM. Stressful stimuli such as a 2-min exposure to diethyl ether and a 30-min restraint produced a marked but transient increase in cortical CCKLM release. In addition, anxiety-like behavior induced by the systemic administration of yohimbine (5 mg/kg i.p.) was associated with a long-lasting enhancement in the peptide outflow. Pretreatment with the potent anxiolytic drug diazepam (5 mg/kg i.p., 5 min before each condition), which exerted no effect on its own, completely prevented CCKLM overflow due to diethyl ether, restraint, or yohimbine administration. In contrast, neither the systemic injection (0.1 mg/kg i.p.) nor the local application (100 microM through the microdialysis probe) of the serotonin 5-HT3 antagonist ondansetron affected the increased release of CCKLM in rats restrained for 30 min or treated with yohimbine. These results indicate that cortical CCKergic neurotransmission is increased during stress or anxiety-like behavior in rats. Prevention of this effect by diazepam suggests that an inhibitory influence of benzodiazepines on cortical CCKergic neurons might participate in the anxiolytic action of these drugs." [Abstract]

Raiteri M, Paudice P, Vallebuona F.
Inhibition by 5-HT3 receptor antagonists of release of cholecystokinin-like immunoreactivity from the frontal cortex of freely moving rats.
Naunyn Schmiedebergs Arch Pharmacol 1993 Jan;347(1):111-4
"Effects of the 5-HT3 receptor antagonists, ondansetron and tropisetron, on the release of cholecystokinin-like immunoreactivity (CCK-LI) in rat frontal cortex were investigated in conscious, unrestrained rats using intracerebral microdialysis. The release of CCK-LI was augmented by perfusion with 100 micrograms/ml veratrine and was fully Ca(2+)-dependent and tetrodotoxin-sensitive. Ondansetron and tropisetron, each at 0.1-1 mumol/l, decreased concentration-dependently the veratrine-evoked efflux of CCK-LI. The reduction of CCK-LI output was approximately 30% when the antagonists were infused at 0.1 mumol/l. The data suggest that 5-HT3 receptor antagonists prevent the release of CCK evoked by endogenous 5-hydroxytryptamine. These drugs may thus represent a novel therapeutic approach in disease states, like anxiety, in which an inappropriately high release of brain CCK or 5-hydroxytryptamine seems to be involved." [Abstract]

Vasar E, Peuranen E, Oopik T, Harro J, Mannisto PT.
Ondansetron, an antagonist of 5-HT3 receptors, antagonizes the anti-exploratory effect of caerulein, an agonist of CCK receptors, in the elevated plus-maze.
Psychopharmacology (Berl) 1993;110(1-2):213-8
"Systemic treatment with caerulein (0.25-5 micrograms/kg SC), non-selective agonist of cholecystokinin (CCK) receptors, dose-dependently suppressed the exploratory behaviour of rats in an elevated plus-maze without producing remarkable changes in the locomotor activity of animals in an open field test. Ondansetron, a selective antagonist of 5-HT3 receptors, increased the number of open arm entries in the plus-maze test only at a dose 10 micrograms/kg. The other doses of ondansetron (0.1, 1 and 100 micrograms/kg IP) did not significantly change either the locomotor activity or the exploratory behaviour of rats. Pretreatment of rats with ondansetron (at 10 micrograms/kg, but not at 0.1, 1 or 100 micrograms/kg) completely reversed the anti-exploratory effect of caerulein (5 micrograms/kg). The concomitant treatment with caerulein and ondansetron did not cause any major change in the locomotor activity of animals in open field. Consequently, we propose that 5-HT-ergic mechanisms are involved not only in the regulation of CCK release in the cerebral cortex and nucleus accumbens, but also in the modulation of the anti-exploratory effect of caerulein, a CCK agonist, in the elevated plus-maze." [Abstract]

van Kampen J, Stoessl AJ.
The effects of CCK-4 on dopamine D1 agonist-induced grooming are blocked by a CCK(A) receptor antagonist: evidence for a novel CCK receptor subtype?
Neuropharmacology 1997 Nov-Dec;36(11-12):1679-88
"The neuropeptide cholecystokinin (CCK) has been shown to interact with dopamine in various ways, including attenuation of dopamine D1 receptor-mediated vacuous chewing and grooming. While we have demonstrated a clear role for the CCK(A) receptor in the attenuation of dopamine D1 agonist-induced vacuous chewing, studies of grooming yielded anomalous results. We examined the effects of selective CCK receptor antagonists on the attenuation of SKF 38393-induced grooming by the CCKB agonist CCK-4. Administration of SKF 38393 (5 mg/kg s.c.) to male Sprague-Dawley rats resulted in a significant increase in grooming which was reduced to control levels by CCK-4 (20 mg/kg i.p.). Pretreatment with either the CCKA receptor antagonist devazepide or the CCK(B) receptor antagonist L-365,260 significantly attenuated this effect over a range of doses (20, 100, 500 microg/kg i.p.). The suppression of dopamine D1 agonist-induced grooming by CCK-4 does not appear to reflect a non-specific effect of anxiogenesis, as it was unaffected by the anxiolytic diazepam. The CCK receptor antagonists alone were without behavioural effect. Taken together with previous studies in models of anxiety and analgesia, our findings lend further support to the hypothesis that CCK-4 may act at a novel receptor subtype." [Abstract]

Ladurelle N, Keller G, Blommaert A, Roques BP, Dauge V.
The CCK-B agonist, BC264, increases dopamine in the nucleus accumbens and facilitates motivation and attention after intraperitoneal injection in rats.
Eur J Neurosci 1997 Sep;9(9):1804-14
"Although it is known that panic attacks are triggered by the cholecystokinin fragment CCK4, the specific involvement of peripheral or central cholecystokinin CCK receptors in various adaptive processes such as emotion, memory and anxiety has yet to be demonstrated. With this aim, we have investigated the biochemical and pharmacological effects resulting from the administration of BC264, a highly potent and selective CCK-B agonist able to cross the blood-brain barrier. Very low doses of BC264 (microg/kg i.p.), increased the exploration of animals submitted to an unknown territory but were devoid of anxiogenic properties in the elevated plus maze. BC264 increased locomotion and rearings of rats newly placed in an open field and improved their spontaneous alternation in a Y-maze. The use of vagotomized animals showed that the increased alternation induced by BC264 did not require an intact vagus nerve, unlike the locomotor activation. These behavioural effects, prevented by the prior i.p. administration of the CCK-B antagonist L-365,260 but not by the CCK-A antagonist L-364,718, were shown to depend on dopaminergic systems, since they were blocked by D1 (SCH23390, 25 microg/kg i.p.) or D2 (sulpiride, 50 or 100 mg/kg i.p.) antagonists. In addition, bilateral perfusion in freely moving rats of BC264 at pharmacologically active doses, using a newly designed microdialysis system, was found to increase the extracellular levels of DA, DOPAC and HVA in the anterior part of the nucleus accumbens. These results show that activation of CCK-B receptors by BC264 does not produce anxiogenic-like effects but appears to improve motivation and attention, whereas other CCK-B agonists such as BocCCK4 induce anxiogenic responses. Several explanations, including the existence of different sub-sites of the CCK-B receptor, could account for these differential effects." [Abstract]

Alan S. Kopin, Edward W. McBride, Michelle C. Gordon, Suzanne M. Quinn, and Martin Beinborn
Inter- and intraspecies polymorphisms in the cholecystokinin-B/gastrin receptor alter drug efficacy
PNAS 94: 11043-11048, 1997.
"The brain cholecystokinin-B/gastrin receptor (CCK-BR) is a major target for drug development because of its postulated role in modulating anxiety, memory, and the perception of pain. Drug discovery efforts have resulted in the identification of small synthetic molecules that can selectively activate this receptor subtype. These drugs include the peptide-derived compound PD135,158 as well as the nonpeptide benzodiazepine-based ligand, L-740,093 (S enantiomer). We now report that the maximal level of receptor-mediated second messenger signaling that can be achieved by these compounds (drug efficacy) markedly differs among species homologs of the CCK-BR. Further analysis reveals that the observed differences in drug efficacy are in large part explained by single or double aliphatic amino acid substitutions between respective species homologs. This interspecies variability in ligand efficacy introduces the possibility of species differences in receptor-mediated function, an important consideration when selecting animal models for preclinical drug testing. The finding that even single amino acid substitutions can significantly affect drug efficacy prompted us to examine ligand-induced signaling by a known naturally occurring human CCK-BR variant (glutamic acid replaced by lysine in position 288; 288E --> K). When examined using the 288E --> K receptor, the efficacies of both PD135,158 and L-740, 093 (S) were markedly increased compared with values obtained with the wild-type human protein. These observations suggest that functional variability resulting from human receptor polymorphisms may contribute to interindividual differences in drug effects." [Full Text]

Benedetti F, Amanzio M, Casadio C, Oliaro A, Maggi G.
Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide.
Pain 1997 Jun;71(2):135-40
"In patients who reported mild postoperative pain, we evoked a nocebo response, a phenomenon equal but opposite to placebo. Patients who gave informed consent to increase their pain for 30 min received a substance known to be non-hyperalgesic (saline solution) and were told that it produced a pain increase. A nocebo effect was observed when saline was administered. However, if a dose of 0.5 or 5 mg of the cholecystokinin antagonist proglumide was added to the saline solution, the nocebo effect was abolished. A dose of 0.05 mg of proglumide was ineffective. The blockade of the nocebo hyperalgesic response was not reversed by 10 mg of naloxone. These results suggest that cholecystokinin mediates pain increase in the nocebo response and that proglumide blocks nocebo through mechanisms not involving opioids. Since the nocebo procedure represents an anxiogenic stimulus and previous studies showed a role for cholecystokinin in anxiety, we suggest that nocebo hyperalgesia may be due to a cholecystokinin-dependent increase of anxiety." [Abstract]

Benedetti F, Amanzio M.
The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin.
Prog Neurobiol. 1997 Jun;52(2):109-25.
"Placebo is a widespread phenomenon in medicine and biology and its mechanisms are understood only partially. Most of our understanding of placebo comes from studies on pain. In particular, placebo analgesia represents a situation where the administration of a substance known to be non-analgesic produces an analgesic response when the subject is told that it is a pain killer. Several theories try to explain this effect by means of anxiety mechanisms, cognitive processes and classical conditioning. However, the placebo response is bidirectional, i.e. analgesic and algesic. In fact, if a subject is told that the ineffective substance is a hyperalgesic drug, a pain increase may occur. The negative effects of placebo are called nocebo and, in extreme cases, they lead to severe pathological conditions. The neurobiology of placebo was born when some authors discovered that placebo analgesia is mediated by endogenous opioids. This claim comes from the observation that the opioid antagonist naloxone can reverse placebo analgesia. On the basis of the discovery of the anti-opioid action of the neuropeptide cholecystokinin, recent studies demonstrate that the blockade of cholecystokinin receptors potentiates the placebo analgesic response, thus suggesting an inhibitory role of cholecystokinin in placebo analgesia. Thus, by antagonizing the anti-opioid action of cholecystokinin during a placebo procedure, a potentiation of the endogenous opioid systems can be obtained." [Abstract]

Brawman-Mintzer O, Lydiard RB, Bradwejn J, Villarreal G, Knapp R, Emmanuel N, Ware MR, He Q, Ballenger JC.
Effects of the cholecystokinin agonist pentagastrin in patients with generalized anxiety disorder.
Am J Psychiatry 1997 May;154(5):700-2
"OBJECTIVE: The anxiogenic and panicogenic effects of peripheral administration of the cholecystokinin-B receptor agonist pentagastrin and placebo were evaluated in patients with generalized anxiety disorder and normal comparison subjects. METHODS: Seven patients with generalized anxiety disorder and seven age- and sex-matched normal subjects received an intravenous bolus of placebo and pentagastrin. RESULTS: Panic attacks occurred in five patients with generalized anxiety disorder (71%) and in one normal subject (14%). Patients with generalized anxiety disorder were more likely to report more nonpanic anxiety than were normal subjects. CONCLUSIONS: Patients with generalized anxiety disorder appear to exhibit greater subjective sensitivity to pentagastrin than do normal subjects." [Abstract]

Pietrowsky R, Rudolf S, Molle M, Fehm HL, Born J.
Cholecystokinin-induced effects on selective attention depend on level of activation.
Neuropsychobiology 1997;36(2):87-95
"Cholecystokinin (CCK)-like peptides, such as ceruletide, have been found to improve selective attention as indicated by the processing negativity (PN) of the event-related brain potential. The present study compared effects of ceruletide and placebo after intravenous administration of ceruletide on the PN in healthy subjects classified into two groups scoring high versus low on self-reported activation. Following placebo, PN (at Fz) was somewhat larger in subjects with low than high activation (p < 0.1). Administration of the CCK analog decreased PN in low-activation subjects but increased PN in the highly activated group (p < 0.01). Results suggest that the effects of CCK on selective attention depend on a modulation of central nervous mechanisms underlying activation." [Abstract]

Mercer LD, Beart PM, Horne MK, Finkelstein DI, Carrive P, Paxinos G.
On the distribution of cholecystokinin B receptors in monkey brain.
Brain Res 1996 Nov 4;738(2):313-8
"In view of recent evidence for a role for the B subtype of cholecystokinin (CCKB) receptor in panic and anxiety, the distribution of CCKB receptors in the forebrain of a Rhesus macaca monkey was examined by receptor autoradiography employing [125I]D-Tyr25(Nleu28,31)-CCK25-33S. CCKB receptors were widely and topographically distributed in cortex. Other structures with notable labelling included the basal ganglia, presubiculum, amygdala, mamillary bodies, cerebellar cortex and pineal gland. The distribution of CCKB receptors further supports roles for this peptide in behavioural processes." [Abstract]

Jenck F, Martin JR, Moreau JL.
Behavioral effects of CCKB receptor ligands in a validated simulation of panic anxiety in rats.
Eur Neuropsychopharmacol 1996 Nov;6(4):291-8 [Abstract]

Raiteri M, Bonanno G, Paudice P, Cavazzani P, Schmid G.
Human brain cholecystokinin: release of cholecystokinin-like immunoreactivity (CCK-LI) from isolated cortical nerve endings and its modulation through GABA(B) receptors.
J Pharmacol Exp Ther 1996 Aug;278(2):747-51
"The release of cholecystokinin-like immunoreactivity (CCK-LI) in human brain was investigated using synaptosomes prepared from neocortical specimens removed during neurosurgery. CCK-LI basal release from superfused synaptosomes was increased 3 to 4-fold during depolarization with 15 mM KCI. The K(+)-evoked overflow of CCK-LI was strictly Ca(++)-dependent. The gamma-aminobutyric acidB (GABA(B)) receptor agonist (-)baclofen (0.3-100 microM) inhibited CCK-LI overflow in a concentration-dependent manner (EC50 = 2.20 microM; maximal effect: 45%). The novel GABA(B) receptor ligand CGP 47656 mimicked (-)baclofen (EC50 = 2.45 microM; maximal effect: 50%), whereas the GABA(A) agonist muscimol was ineffective up to 100 microM. The inhibitory effect of 10 microM (-)baclofen on the CCK-LI overflow was concentration-dependently prevented by two selective GABA(B) receptor antagonists, CGP 35348 (IC50 = 13.91 microM) and CGP 52432 (IC50 = 0.08 microM). The effect of 10 microM CGP 47656 was abolished by 1 microM CGP 52432. In experiments on [3H]GABA release, CGP 47656 behaved as an antagonist at the GABA(B) autoreceptors: added at 10 microM, it prevented the inhibitory effect of 10 microM (-)baclofen on the K+ (15 mM)-evoked release of [3H]GABA from human synaptosomes. We conclude that 1) the release of CCK-LI evoked from human brain tissue appears of neuronal origin; 2) the CCK-releasing terminal possess inhibitory presynaptic GABA(B) receptors; 3) these receptors differ pharmacologically from human neocortex GABA(B) autoreceptors, which are CGP 35348-insensitive (Fassio et al., 1994) but can be blocked by CGP 47656; 4) because cholecystokinin has been implicated in anxiety, the GABA(B) receptors here characterized may represent targets for novel anxiolytic agents." [Abstract]

Josselyn SA, Frankland PW, Petrisano S, Bush DE, Yeomans JS, Vaccarino FJ.
The CCKB antagonist, L-365,260, attenuates fear-potentiated startle.
Peptides 1995;16(7):1313-5
"The neuropeptide cholecystokinin (CCK), via the CCKB receptor, increases behaviors associated with anxiety in laboratory animals and humans. The present experiment assessed the role of endogenous CCKB function in fear-potentiated startle, a test of "anxiety" in rats. The amplitude of the acoustic startle response is potentiated if preceded by a stimulus that has been previously paired with shock. Pretreatment with the CCKB antagonist L-365,260 (0, 0.1, 1.0, and 10.0 mg/kg, IP) did not affect baseline acoustic startle amplitudes, but dose-dependently decreased fear-potentiated startle. These results indicate that the specific attenuation of fear-potentiated startle induced by L-365,260 was not due to a general decrease in motor responsivity. The present findings are consistent with the effects of CCKB antagonists in other tests measuring anxiety in animals." [Abstract]

Fendt M, Koch M, Kungel M, Schnitzler HU.
Cholecystokinin enhances the acoustic startle response in rats.
Neuroreport 1995 Oct 23;6(15):2081-4
"The present study examined the effects of the neuropeptide cholecystokinin (CCK) on neurones of the caudal pontine reticular nucleus (PnC), which mediates the acoustic startle response (ASR) in rats. Electrophysiological experiments revealed an excitatory effect of CCK on acoustically responsive neurones in the PnC. On the behavioural level, CCK also enhanced the ASR. Since the PnC is not only an obligatory relay station of the brain circuit mediating the ASR, but also receives modulatory input from brain areas involved in the expression of fear and anxiety, the enhancement of the ASR by CCK could be interpreted as an anxiogenic-like effect of this peptide." [Abstract]

Benkelfat C, Bradwejn J, Meyer E, Ellenbogen M, Milot S, Gjedde A, Evans A.
Functional neuroanatomy of CCK4-induced anxiety in normal healthy volunteers.
Am J Psychiatry 1995 Aug;152(8):1180-4
"OBJECTIVE: The authors tested the prediction of temporal cortex activation during experimentally induced anxiety by using positron emission tomography and the [15O]H2O bolus-subtraction method to determine regional cerebral blood flow (CBF) changes in normal volunteers challenged with a bolus injection of cholecystokinin tetrapeptide (CCK4). METHOD: Eight right-handed healthy subjects (five male, three female; mean age, 26.4 years) underwent four 60-second [15O]H2O scans separated by 15-minute intervals; each scan followed an intravenous bolus injection of either saline (placebo) or CCK4 (50 micrograms). Each subject received CCK4 once, as the first or second bolus, in a random-order, placebo-controlled, double-blind fashion. Two of the three placebo conditions were nominally identical, and the remaining placebo was used to control for anticipatory anxiety. Magnetic resonance imaging scans were obtained for subsequent anatomical correlation of blood flow changes. RESULTS: CCK4, but not placebo, elicited a marked anxiogenic response, reflected by robust increases in subjective anxiety ratings and heart rate. CCK4-induced anxiety was associated with 1) robust and bilateral increases in extracerebral blood flow in the vicinity of the superficial temporal artery territory and 2) CBF increases in the anterior cingulate gyrus, the claustrum-insular-amygdala region, and the cerebellar vermis. CONCLUSIONS: Some of the temporopolar cortex CBF activation peaks previously reported in humans in association with drug- and non-drug-induced anxiety, as well as the increase in regional CBF in the claustrum-insular-amygdala region, may be of vascular and/or muscular origin." [Abstract]

Pratt JA, Brett RR.
The benzodiazepine receptor inverse agonist FG 7142 induces cholecystokinin gene expression in rat brain.
Neurosci Lett 1995 Jan 30;184(3):197-200
"The effects of acute administration of the anxiogenic benzodiazepine receptor ligand, N-methyl-beta-carboline-3-carboxamide (FG 7142) and of a single exposure to the elevated plus-maze test of anxiety on preprocholecystokinin mRNA levels in rat brain were examined using the technique of in situ hybridisation. Administration of FG 7142 (10 mg/kg i.p.), but not elevated plus-maze exposure, increased cholecystokinin (CCK) mRNA levels in the basolateral amygdala and the CA3 pyramidal cell layer of the hippocampus. Neither stimulus produced changes in thalamic structures. These data suggest that drug-induced anxiety can induce CCK gene expression in brain structures previously implicated in anxiety." [Abstract]

Belzung C, Pineau N, Beuzen A, Misslin R.
PD135158, a CCK-B antagonist, reduces "state," but not "trait" anxiety in mice.
Pharmacol Biochem Behav 1994 Oct;49(2):433-6
"It has recently been proposed that Balb/c neophobic responses in a free exploratory paradigm are related to "trait" anxiety, while the behavior of mice in the light/dark choice test paradigm is related to "state" anxiety. The purpose of this study was to assess the action of the CCK-B receptor antagonist PD135158 in both models. Results show that PD135158 was effective in the light/dark choice test but not on the Balb/c neophobic reactions in the free exploratory situation. It is suggested that PD135158 is specially effective in state anxiety induced by fear provoking situations." [Abstract]

Harro J, Wahlstrom G, Oreland L.
Cholecystokinin receptor binding after long-term ethanol treatment in rats.
Alcohol Alcohol 1994 Sep;29(5):575-81
"Brain cholecystokinin (CCK) receptors have been implicated in anxiety disorders and suicidal behaviour. We have examined the radioligand binding ability of CCK and benzodiazepine receptors in rat brain after long-term intermittent voluntary vs voluntary and forced low-dose ethanol exposure. During 58 weeks, one group of rats had a choice between ethanol and water as the drinking fluid for 24 hr each week. Another group of rats had the same weekly choice between ethanol and water, but at the end of each 24 hr choice period, ethanol (2.0 g/kg) was injected. During the second period of ethanol treatment, lasting for 32 weeks, both ethanol-treated groups had continuous free access to ethanol and water. These two treatments have previously been shown to induce partially different neurochemical alterations. In the present investigation, benzodiazepine receptor binding in the frontal cortex, hippocampus and striatum was similar in both ethanol treatment groups compared to controls. CCK receptor binding in the hippocampus and striatum did not differ between the three groups; however, in the frontal cortex, there was an increase in the apparent number of CCK binding sites in the group of rats submitted to voluntary plus forced ethanol exposure as compared to the control group or the voluntary intake group. These results suggest that long-term ethanol treatment may lead to alterations in brain CCK-ergic neurotransmission, but that the changes are specific to the treatment schedule." [Abstract]

Abelson JL, Nesse RM.
Pentagastrin infusions in patients with panic disorder. I. Symptoms and cardiovascular responses.
Biol Psychiatry 1994 Jul 15;36(2):73-83
"Cholecystokinin (CCK) may mediate human anxiety and animal data suggest that cholecystokinin antagonists could provide an important advance in the treatment of anxiety disorders. The study of CCK receptor systems in psychiatric patients has, however, been severely limited by the lack of available probes. We utilized intravenous infusions of pentagastrin, a selective CCK-B receptor agonist, and studied behavioral and cardiovascular responses in 10 patients with panic disorder and 10 normal controls. Pentagastrin produced substantial symptomatology, including anxiety, and increases in heart rate and blood pressure, in both patients and controls. Patients were more sensitive to the panicogenic effects of the pentagastrin. Panic attacks occurred in 70% of patients and 0% of controls. Patients' symptom responses were very similar to their "typical" panic attacks and to symptoms produced by CCK4. Pentagastrin provides a readily available alternative to CCK4 for studying the CCK receptor system and exploring its involvement in human anxiety." [Abstract]

Vasar E, Lang A, Harro J, Bourin M, Bradwejn J.
Evidence for potentiation by CCK antagonists of the effect of cholecystokinin octapeptide in the elevated plus-maze.
Neuropharmacology 1994 Jun;33(6):729-35
"Systemic treatment with cholecystokinin octapeptide (CCK-8, 2.5-10 micrograms/kg, s.c.), a non-selective CCK agonist, decreased the exploratory activity of mice in an elevated plus-maze. At higher doses (5-10 micrograms/kg) CCK-8 reduced the frequency of rearing, but only 10 micrograms/kg of CCK-8 significantly inhibited the number of line crossings in the open-field test. A preferential CCKB antagonist L-365,260 (1 and 100 micrograms/kg, i.p.) and a non-selective CCK antagonist proglumide (0.1-1 microgram/kg, i.p.) potentiated the anti-exploratory effect of CCK-8 (2.5 micrograms/kg). Devazepide, a preferential CCKA antagonist, only at a high dose (100 micrograms/kg) tended to increase the action of CCK-8 in the plus-maze. However, the concomitant treatment of CCK-8 with L-365,260 and proglumide, differently from devazepide, also suppressed the locomotor activity in the open-field test. Therefore, it is likely that the potentiation by CCK antagonists of the anti-exploratory effect of CCK-8 is related to the suppression of motor activity. This peculiar interaction between CCK-8 and CCK antagonists could be explained in the light of the opposite role of CCKA and CCKB receptors in the regulation of motor activity in mice." [Abstract]

Rex A, Barth T, Voigt JP, Domeney AM, Fink H.
Effects of cholecystokinin tetrapeptide and sulfated cholecystokinin octapeptide in rat models of anxiety.
Neurosci Lett 1994 May 19;172(1-2):139-42
"The effects of the acutely administered cholecystokinin (CCK) agonists CCK tetrapeptide (BOC-CCK-4) and sulfated CCK octapeptide (CCK-8S) were examined in four animal models of anxiety in rats. In the elevated plus maze, BOC-CCK-4 reduced the time spent in the open arms and the number of entries into the open arms. BOC-CCK-4 but not the anorectic acting CCK-8S increased the suppression of feeding in a conflict paradigm based on novelty suppressed feeding in hungry rats. In the two-compartment black-and-white box, BOC-CCK-4 decreased the time spent and locomotor activity in the white compartment. In the ultrasound vocalization test, using rat pups separated from the mother, BOC-CCK-4 increased the number of distress calls. No evidence was found for inducing anxiety-like behaviour by CCK-8S." [Abstract]

Xu XJ, Hao JX, Seiger A, Hughes J, Hokfelt T, Wiesenfeld-Hallin Z.
Chronic pain-related behaviors in spinally injured rats: evidence for functional alterations of the endogenous cholecystokinin and opioid systems.
Pain 1994 Mar;56(3):271-7
"We have recently developed a rat model of chronic pain states after spinal cord injury. Thus, after severe, but incomplete, ischemic spinal cord injury, some rats chronically exhibited responses indicative of pain to innocuous mechanical stimuli (allodynia) in the rostral dermatomes involving the injured spinal segments. These responses have some characteristics in common with chronic central pain in patients with spinal cord injury. We now report that systemic CI988, a specific antagonist of the cholecystokinin (CCK) type B receptor, effectively relieved the allodynia-like symptom, an effect that was reversed by the opioid receptor antagonist naloxone. Furthermore, in rats which did not develop the allodynia-like symptom after spinal cord lesion, systemic naloxone induced typical allodynia. In contrast, naloxone failed to produce allodynia in normal animals. It is thus suggested that the abnormal sensory processing initiated by spinal cord ischemic lesion is under tonic opioidergic control and dysfunction of this control by the upregulated endogenous CCK system is responsible for the development of painful sensations in these rats." [Abstract]

Vasar E, Peuranen E, Harro J, Lang A, Oreland L, Mannisto PT.
Social isolation of rats increases the density of cholecystokinin receptors in the frontal cortex and abolishes the anti-exploratory effect of caerulein.
Naunyn Schmiedebergs Arch Pharmacol 1993 Jul;348(1):96-101
"The role of cholecystokinin (CCK) receptors in the development of anxiety caused by social isolation of rats was studied using the elevated plus-maze and receptor binding techniques. The isolation of male Wistar rats significantly reduced their exploratory activity in the elevated plus-maze compared with that of rats kept in groups of four. Caerulein (0.1-5 micrograms/kg s.c.), an agonist at CCK receptors, only at the highest dose (5 micrograms/kg) significantly decreased the exploratory behaviour of rats housed in groups, but not in the isolated rats. By contrast, small doses of caerulein (0.1-0.5 microgram/kg) even tended to increase the behavioural activity of isolated rats in the plus-maze test. In parallel to the behavioural changes, isolation of the rats increased the number of [3H]pCCK-8 binding sites in the frontal cortex, but not in the other forebrain structures (the mesolimbic area, striatum and hippocampus). Isolation did not affect the density of benzodiazepine receptors in the frontal cortex. In conclusion, the isolation of rats for 7 days produced anxiogenic-like effect on the behaviour of rats and increased the number of CCK receptors in the frontal cortex without affecting benzodiazepine receptors." [Abstract]

Harro J, Marcusson J, Oreland L.
Alterations in brain cholecystokinin receptors in suicide victims.
Eur Neuropsychopharmacol 1992 Mar;2(1):57-63
"Cholecystokinin (CCK) and benzodiazepine receptor binding characteristics were analyzed in the brain tissue samples from 19 suicide victims and 23 control cases. In the frontal cortex, significantly higher apparent number of CCK receptors and affinity constants were found in the series of suicide victims. These differences between suicides and controls were present in similar proportions when the suicide cases with depressive syndrome or violent or non-violent means of self-killing were compared to matched controls. However, when the samples were split into subgroups consisting of persons either below or over the age of 60 years, significant differences in the CCK receptor characteristics in the frontal cortex were observed only between younger suicides and controls. Furthermore, the younger suicide victims had a higher density of CCK receptors in the cingulate cortex, whereas in older suicides the value was lower as compared to age-matched controls. No difference in benzodiazepine receptor binding was found between control and suicide groups. The results of this investigation suggest that CCK-ergic neurotransmission is linked to self-destructive behaviour, probably through its impact on anxiety and adaptational deficits." [Abstract]

Branchereau P, Bohme GA, Champagnat J, Morin-Surun MP, Durieux C, Blanchard JC, Roques BP, Denavit-Saubie M.
CholecystokininA and cholecystokininB receptors in neurons of the brainstem solitary complex of the rat: pharmacological identification.
J Pharmacol Exp Ther 1992 Mar;260(3):1433-40
"The brainstem solitary complex, which receives projections from primary sensory afferents of the vagus nerve, appears to be a crucial site for the action of the cholecystokinin octapeptide (CCK8), because both peripheral-type (CCKA) and central-type (CCKB) binding sites are present in this structure. In the present study, we investigated the effects of recently developed receptor-specific pharmacological tools on neurons recorded in rat coronal brainstem slices, to ascertain whether CCK acts differently on each type of receptor. CCK8, which interacts with both binding sites, had three effects on neuronal discharge, brief excitation, prolonged excitation and delayed inhibition. BC 264, a novel CCK analog endowed with high affinity and selectivity for CCKB receptors, produced exclusively prolonged excitation. L-365,260, a novel nonpeptide antagonist of CCKB receptors, blocked the prolonged excitation induced by BC 264 or CCK8. L-364,718, a potent antagonist of CCKA receptors, blocked delayed inhibition and replaced brief CCK8-induced excitation by prolonged excitation. Altogether, these results show that CCK8 exerts, on neurons of the solitary complex, mixed effects due to simultaneous activation of CCKA inhibitory and CCKB excitatory binding sites. The hypothesis that exogenous CCK8 acts, in the solitary complex, through CCKA sites to slow down the motility of the digestive tract and through CCKB sites to modulate anxiety will be developed." [Abstract]

Kellner M, Yassouridis A, Hua Y, Wendrich M, Jahn H, Wiedemann K.
Intravenous C-type natriuretic peptide augments behavioral and endocrine effects of cholecystokinin tetrapeptide in healthy men.
J Psychiatr Res 2002 Jan-Feb;36(1):1-6 [Abstract]

Strohle A, Kellner M, Holsboer F, Wiedemann K.
Anxiolytic activity of atrial natriuretic peptide in patients with panic disorder.
Am J Psychiatry 2001 Sep;158(9):1514-6 [Abstract]

Wiedemann K, Jahn H, Kellner M.
Effects of natriuretic peptides upon hypothalamo-pituitary-adrenocortical system activity and anxiety behaviour.
Exp Clin Endocrinol Diabetes 2000;108(1):5-13 [Abstract]

Miyasaka, Kyoko, Ichikawa, Mineko, Ohta, Minoru, Kanai, Setsuko, Yoshida, Yuki, Masuda, Masao, Nagata, Aki, Matsui, Toshimitsu, Noda, Tetsuo, Takiguchi, Soichi, Takata, Yutaka, Kawanami, Takako, Funakoshi, Akihiro
Energy Metabolism and Turnover Are Increased in Mice Lacking the Cholecystokinin-B Receptor
J. Nutr. 2002 132: 739-741
"Cholecystokinin (CCK) is an important gastrointestinal hormone as well as a neurotransmitter. Two types of CCK receptors, types A and B, have been identified. The CCK-A receptor is involved in satiety, food intake and behavior, whereas the B receptor is involved in anxiety. We recently produced CCK-A, -B and AB receptor knockout mice to study the role of these receptors in energy metabolism. Daily energy intake and expenditure were significantly greater in CCK-BR(-/-) and CCK-AR(-/-)BR(-/-) mice than CCK-AR(-/-) and wild-type [CCK-AR(+/+)BR(+/+)] mice. Relative liver and kidney weights (g/kg body) were significantly greater in CCK-AR(-/-)BR(-/-) mice than in wild-type mice. Energy metabolism and energy turnover were increased in mice with a disruption of the CCK-BR gene, although the underlying mechanism is unknown. " [Abstract]


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Recent Cholecystokinin and Anxiety Research

1) Plag J, Gaudlitz K, Zschucke E, Yassouridis A, Pyrkosch L, Wittmann A, Holsboer F, Ströhle A
Distinct panicogenic activity of sodium lactate and cholecystokinin tetrapeptide in patients with panic disorder.
Curr Pharm Des. 2012 May 24;
Background: The validity of experimentally induced panic attacks as a model to study the pathophysiology of panic disorder has been questioned. Unspecific, unpleasant and aversive effects as well as specific patterns of psychovegetative symptoms pointing to different subtypes of panic disorder patients have been observed. These findings raise the question of challenge paradigms as a valuable tool to identify different vulnerabilities in patients with panic disorder. Methods: We compared the two most widely studied panicogenic drugs sodium lactate and cholecystokinine tetrapeptide (CCK-4) with placebo in 25 patients with panic disorder and matched healthy control subjects. Psychophysiological changes were measured using the Acute Panic Inventory (API) and visual analogue scales for anxiety and arousal. Results: In patients with panic disorder 18 out of 25 experienced a sodium lactate- or a CCK-4 induced panic attack. Lactate or CCK-4 induced symptoms and induced panic attacks were only correlated in healthy controls, but not in patients with panic disorder. Conclusion: The mechanisms of lactate and CCK-4 induced panic attacks are distinct in panic disorder patients but not in healthy controls. Different neurobiological vulnerabilities may be uncovered by different challenges. [PubMed Citation] [Order full text from Infotrieve]

2) Del Boca C, Lutz PE, Le Merrer J, Koebel P, Kieffer BL
Cholecystokinin knock-down in the basolateral amygdala has anxiolytic and antidepressant-like effects in mice.
Neuroscience. 2012 Aug 30;218:185-95.
Cholecystokinin (CCK) is a neuropeptide widely distributed in the mammalian brain. This peptide regulates many physiological functions and behaviors, such as cardio-respiratory control, thermoregulation, nociception, feeding, memory processes and motivational responses, and plays a prominent role in emotional responses including anxiety and depression. CCK-expressing brain regions involved in these functions remain unclear and their identification represents an important step towards understanding CCK function in the brain. The basolateral amygdala (BLA) is strongly involved in emotional processing and expresses high levels of CCK. In this study we examined the contribution of CCK expressed in this brain region to emotional responses in mice. To knockdown CCK specifically in the BLA, we used stereotaxic delivery of recombinant adeno-associated viral vectors expressing a CCK-targeted shRNA. This procedure efficiently reduced CCK levels locally. shCCK-treated animals showed reduced levels of anxiety in the elevated plus-maze, and lower despair-like behavior in the forced swim test. Our data demonstrate that CCK expressed in the BLA represents a key brain substrate for anxiogenic and depressant effects of the peptide. The study also suggests that elevated amygdalar CCK could contribute to panic and major depressive disorders that have been associated with CCK dysfunction in humans. [PubMed Citation] [Order full text from Infotrieve]

3) Hajizadeh Moghaddam A, Hosseini RS, Roohbakhsh A
Anxiogenic effect of CCK8s in the ventral hippocampus of rats: possible involvement of GABA(A) receptors.
Pharmacol Rep. 2012;64(1):45-53.
Cholecystokinin (CCK) as an important neuropeptide in the brain has been implicated in the modulation of anxiety. The effects of this neurotransmitter on anxiety-like behavior in the ventral hippocampus have not been evaluated yet. Moreover, some evidences show a functional interaction between GABA and CCK in the nervous system. Bilateral injections of three doses of CCK8s (0.01, 0.05 and 0.1 ?g/rat) into the ventral hippocampus decreased percentage of open arm time (%OAT) and open arm entries (%OAE) that are representative of anxiogenic-like behavior in the elevated plus-maze test of anxiety. Bilateral injections of LY225910, a selective CCK(2) receptor antagonist, at the doses of 0.01, 0.1 and 0.5 ?g/rat did not change anxiety-related parameters. Administration of muscimol, a selective GABA(A) receptor agonist, at the doses of 0.001, 0.005 and 0.01 ?g/rat produced dose dependent increase in %OAT and %OAE indicating an anxiolytic-like effect, while administration of bicuculline, a selective GABA(A) receptor antagonist, at the doses of 0.1, 0.2 and 0.5 ?g/rat decreased %OAT and %OAE showing that this drug promoted anxious behavior of the rats. Co-administration of bicuculline (0.2 ?g/rat) with CCK8s decreased the anxiogenic effects of CCK8s. Furthermore, co-administration of LY225910 (0.5 ?g/rat) with muscimol increased the anxiolytic effect of muscimol at the dose of 0.001 ?g/rat. The results of this study suggest that both CCK and GABAergic system have important and opposite roles in the modulation of anxiety-like behavior in the ventral hippocampus of rats and they may have a complex interaction in the ventral hippocampus to modulate anxiety-related behavior. [PubMed Citation] [Order full text from Infotrieve]

4) Zwanzger P, Domschke K, Bradwejn J
Depress Anxiety. 2012 May 2;
Panic disorder (PD) is characterized by panic attacks, anticipatory anxiety and avoidance behavior. Its pathogenesis is complex and includes both neurobiological and psychological factors. With regard to neurobiological underpinnings, anxiety in humans seems to be mediated through a neuronal network, which involves several distinct brain regions, neuronal circuits and projections as well as neurotransmitters. A large body of evidence suggests that the neuropeptide cholecystokinin (CCK) might be an important modulator of this neuronal network. Key regions of the fear network, such as amygdala, hypothalamus, peraqueductal grey, or cortical regions seem to be connected by CCKergic pathways. CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS. In humans, administration of CCK-4 reliably provokes panic attacks, which can be blocked by antipanic medication. Also, there is some support for a role of the CCK system in the genetic pathomechanism of PD with particularly strong evidence for the CCK gene itself and the CCK-2R (CCKBR) gene. Thus, it is hypothesized that genetic variants in the CCK system might contribute to the biological basis for the postulated CCK dysfunction in the fear network underlying PD. Taken together, a large body of evidence suggests a possible role for the neuropeptide CCK in PD with regard to neuroanatomical circuits, neurotransmitters and genetic factors. This review article proposes an extended hypothetical model for human PD, which integrates preclinical and clinical findings on CCK in addition to existing theories of the pathogenesis of PD. [PubMed Citation] [Order full text from Infotrieve]

5) Erlich JC, Bush DE, Ledoux JE
The role of the lateral amygdala in the retrieval and maintenance of fear-memories formed by repeated probabilistic reinforcement.
Front Behav Neurosci. 2012;6:16.
The lateral nucleus of the amygdala (LA) is a key element in the neural circuit subserving Pavlovian fear-conditioning, an animal model of fear and anxiety. Most studies have focused on the role of the LA in fear acquisition and extinction, i.e., how neural plasticity results from changing contingencies between a neutral conditioned stimulus (CS) (e.g., a tone) and an aversive unconditioned stimulus (US) (e.g., a shock). However, outside of the lab, fear-memories are often the result of repeated and unpredictable experiences. Examples include domestic violence, child abuse or combat. To better understand the role of the LA in the expression of fear resulting from repeated and uncertain reinforcement, rats experienced a 30% partial reinforcement (PR) fear-conditioning schedule four days a week for four weeks. Rats reached asymptotic levels of conditioned-fear expression after the first week. We then manipulated LA activity with drug (or vehicle) (VEH) infusions once a week, for the next three weeks, before the training session. LA infusions of muscimol (MUSC), a GABA-A agonist that inhibits neural activity, reduced CS evoked fear-behavior to pre-conditioning levels. LA infusions of pentagastrin (PENT), a cholecystokinin-2 (CCK) agonist that increases neural excitability, resulted in CS-evoked fear-behavior that continued past the offset of the CS. This suggests that neural activity in the LA is required for the retrieval of fear memories that stem from repeated and uncertain reinforcement, and that CCK signaling in the LA plays a role in the recovery from fear after the removal of the fear-evoking stimulus. [PubMed Citation] [Order full text from Infotrieve]

6) Bowers ME, Choi DC, Ressler KJ
Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y.
Physiol Behav. 2012 Mar 10;
The neural circuitry of fear likely underlies anxiety and fear-related disorders such as specific and social phobia, panic disorder, and posttraumatic stress disorder. The primary pharmacological treatments currently utilized for these disorders include benzodiazepines, which act on the GABAergic receptor system, and antidepressants, which modulate the monamine systems. However, recent work on the regulation of fear neural circuitry suggests that specific neuropeptide modulation of this system is of critical importance. Recent reviews have examined the roles of the hypothalamic-pituitary-adrenal axis neuropeptides as well as the roles of neurotrophic factors in regulating fear. The present review, instead, will focus on three neuropeptide systems which have received less attention in recent years but which are clearly involved in regulating fear and its extinction. The endogenous opioid system, particularly activating the ? opioid receptors, has been demonstrated to regulate fear expression and extinction, possibly through functioning as an error signal within the ventrolateral periaqueductal gray to mark unreinforced conditioned stimuli. The cholecystokinin (CCK) system initially led to much excitement through its potential role in panic disorder. More recent work in the CCK neuropeptide pathway suggests that it may act in concordance with the endogenous cannabinoid system in the modulation of fear inhibition and extinction. Finally, older as well as very recent data suggests that neuropeptide Y (NPY) may play a very interesting role in counteracting stress effects, enhancing extinction, and enhancing resilience in fear and stress preclinical models. Future work in understanding the mechanisms of neuropeptide functioning, particularly within well-known behavioral circuits, are likely to provide fascinating new clues into the understanding of fear behavior as well as suggesting novel therapeutics for treating disorders of anxiety and fear dysregulation. [PubMed Citation] [Order full text from Infotrieve]

7) Koszycki D, Prichard Z, Fiocco AJ, Shlik J, Kennedy JL, Bradwejn J
CCK-B receptor gene and response to cholecystokinin-tetrapeptide in healthy volunteers.
Peptides. 2012 May;35(1):9-13.
Recent investigations suggest that genes that confer risk for panic disorder (PD) may moderate response to panicogenic agents in healthy volunteers. Given the potential role of the central cholecystokinin receptor (CCKBR) (CT) polymorphism alleles 26 and 27 in PD, the present study attempted to discern if these alleles moderated panicogenic sensitivity to the CCKBR agonist, CCK-tetrapeptide (CCK-4), in healthy volunteers. The study group consisted of 92 men and women with no personal or family history of psychiatric illness. Participants provided blood samples for genotyping of the CCKBR alleles and they received a 25 ?g bolus injection of CCK-4. Behavioral, cardiovascular and hormonal responses to the peptide were assessed and analyzed with adjusted linear regression models. Carriers of the CCKBR alleles tended to have higher levels of pre-challenge anxiety and significantly higher levels of anxiety sensitivity and introversion than those without the alleles. However, they did not exhibit an enhanced panicogenic response to CCK-4. Overall, our findings do not demonstrate a role of these alleles in modulating CCK-4's panicogenicity. The significant association between the risk alleles and anxiety-related personality traits is intriguing and further exploration of this association is merited. [PubMed Citation] [Order full text from Infotrieve]

8) Kellner M
Experimental panic provocation in healthy man-a translational role in anti-panic drug development?
Dialogues Clin Neurosci. 2011;13(4):485-93.
Experimental neurochemical provocation of panic attacks in susceptible human subjects has considerably expanded our knowledge of the pathophysiology and psychopharmacology of panic disorder. Some panicogens also elicit short-lived panic-like states in healthy man. This offers the opportunity to assess the anti-panic action of drugs in proof-of-concept studies. However, from current data it is still unclear whether experimental panic in healthy man is a valid translational model. Most such studies in healthy volunteers have been performed using a cholecystokinin tetrapeptide (CCK-4) challenge. While CCK-4 panic was blocked by alprazolam pretreatment, escitalopram showed negative results in healthy man. Preliminary findings on novel investigational drugs and a few problematic results will be reviewed. Small sample sizes in many panic provocation studies, lack of dose-response aspects, and still-insufficient knowledge about the biological underpinning of experimental and spontaneous panic limit the interpretation of existing findings and should inspire further research. [PubMed Citation] [Order full text from Infotrieve]

9) Demiralay C, Jahn H, Kellner M, Yassouridis A, Wiedemann K
Differential effects to CCK-4-induced panic by dexamethasone and hydrocortisone.
World J Biol Psychiatry. 2011 Nov 23;
Objectives. Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic-pituitary-adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared. Methods. Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed. Results. We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level. Conclusions. Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4. [PubMed Citation] [Order full text from Infotrieve]

10) Xiao Z, Jaiswal MK, Deng PY, Matsui T, Shin HS, Porter JE, Lei S
Requirement of phospholipase C and protein kinase C in cholecystokinin-mediated facilitation of NMDA channel function and anxiety-like behavior.
Hippocampus. 2012 Jun;22(6):1438-50.
Although cholecystokinin (CCK) has long been known to exert anxiogenic effects in both animal anxiety models and humans, the underlying cellular and molecular mechanisms are ill-defined. CCK interacts with CCK-1 and CCK-2 receptors resulting in up-regulation of phospholipase C (PLC) and protein kinase C (PKC). However, the roles of PLC and PKC in CCK-mediated anxiogenic effects have not been determined. We have shown previously that CCK facilitates glutamate release in the hippocampus especially at the synapses formed by the perforant path and dentate gyrus granule cells via activations of PLC and PKC. Here we further demonstrated that CCK enhanced NMDA receptor function in dentate gyrus granule cells via activation of PLC and PKC pathway. At the single-channel level, CCK increased NMDA single-channel open probability and mean open time, reduced the mean close time, and had no effects on the conductance of NMDA channels. Because elevation of glutamatergic functions results in anxiety, we explored the roles of PLC and PKC in CCK-induced anxiogenic actions using the Vogel Conflict Test (VCT). Our results from both pharmacological approach and knockout mice demonstrated that microinjection of CCK into the dentate gyrus concentration-dependently increased anxiety-like behavior via activation of PLC and PKC. Our results provide a novel unidentified signaling mechanism whereby CCK increases anxiety. [PubMed Citation] [Order full text from Infotrieve]

11) McGonigle P
Peptide therapeutics for CNS indications.
Biochem Pharmacol. 2012 Mar 1;83(5):559-66.
Neuropeptides play a crucial role in the normal function of the central nervous system and peptide receptors hold great promise as therapeutic targets for the treatment of several CNS disorders. In general, the development of peptide therapeutics has been limited by the lack of drug-like properties of peptides and this has made it very difficult to transform them into marketable therapeutic molecules. Some of these challenges include poor in vivo stability, poor solubility, incompatibility with oral administration, shelf stability, cost of manufacture. Recent technical advances have overcome many of these limitations and have led to rapid growth in the development of peptides for a wide range of therapeutic indications such as diabetes, cancer and pain. This review examines the therapeutic potential of peptide agonists for the treatment of major CNS disorders such as schizophrenia, anxiety, depression and autism. Both clinical and preclinical data has been accumulated supporting the potential utility of agonists at central neurotensin, cholecystokinin, neuropeptide Y and oxytocin receptors. Some of the successful approaches that have been developed to increase the stability and longevity of peptides in vivo and improve their delivery are also described and potential strategies for overcoming the major challenge that is unique to CNS therapeutics, penetration of the blood-brain barrier, are discussed. [PubMed Citation] [Order full text from Infotrieve]

12) Wilson J, Markie D, Fitches A
Cholecystokinin system genes: associations with panic and other psychiatric disorders.
J Affect Disord. 2012 Feb;136(3):902-8.
[PubMed Citation] [Order full text from Infotrieve]

13) Rünkorg K, Orav L, Kõks S, Matsui T, Volke V, Vasar E
Rimonabant attenuates amphetamine sensitisation in a CCK2 receptor-dependent manner.
Behav Brain Res. 2012 Jan 1;226(1):335-9.
In this behavioural and pharmacological study in male CCK2 receptor-deficient mice (CCK2(-/-)), we evaluated the role of the interaction of endocannabinoids (eCBs) and cholecystokinin (CCK) on the regulation of anxiety-related and motor behaviours. Repeated treatment with amphetamine (2mg/kg daily for four days) induced slightly weaker motor sensitisation in CCK2(-/-) mice compared to their wild-type (CCK2(+/+)) littermates. Co-administration of rimonabant (1mg/kg) with amphetamine antagonised the development of motor sensitisation in CCK2(+/+) mice. However, we did not find a similar effect of rimonabant in CCK2(-/-) mice. We did not find any differences between the behaviour of CCK2(+/+) and CCK2(-/-) mice in models designed to assess emotional behaviours (dark/light exploration, marble burying and conditioned place aversion). This study supports the hypothesis that eCBs play a role in the development of amphetamine-induced sensitisation. Moreover, we have demonstrated that intact CCK2 receptors are necessary for the development of eCB-mediated sensitisation to amphetamine. [PubMed Citation] [Order full text from Infotrieve]

14) Kolik LG, Garibova TL, Litvinova SA, Kuznetsova AL, Kapitsa IG, Kadnikov IA, Konstantinopol'skiĭ MA, Gudasheva TA, Voronina TA, Seredenin SB
[The absence of tolerance and withdrawal syndrome after the treatment with the new L-tryptophane-containing dipeptide anxiolytic GB-115].
Vestn Ross Akad Med Nauk. 2011;(7):37-42.
Effects of GB-115, an anxiolytic L-triptophan-containing dipeptide, based on the endogenous tetrapeptide cholecystokinin, were evaluated during and after withdrawal of its long-term administration to rats in comparison with diazepam. It was shown using the "elevated plus-maze" test (EPM) that GB-115 retained its anxiolytic properties after i/p injections at a daily dose of 0.1 mg/kg fo r 30-days. Discontinuation of dipeptide administration 24h and 48 hours after the onset of the experiment did not lead to behavioral (increased anxiety, aggression) and convulsive (decreased corazol sensitivity) manifestations of withdrawal syndrome. In contrast, the withdrawal ofdiazepam (4.0 mg/kg/day, ip, 30 days) induced the anxiogenic response in EPM, reduction of the aggression threshold, and enhancement of convulsive readiness. Significant differences between GB-115 and diazepam effects on the levels of dopamine, norepinephrine, and their metabolites after chronic administration and withdrawal were restricted to striatum. [PubMed Citation] [Order full text from Infotrieve]

15) Na HR, Kang EH, Lee JH, Yu BH
The genetic basis of panic disorder.
J Korean Med Sci. 2011 Jun;26(6):701-10.
Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. Linkage studies have implicated several chromosomal regions, but no research has replicated evidence for major genes involved in panic disorder. Researchers have suggested several neurotransmitter systems are related to panic disorder. However, to date no candidate gene association studies have established specific loci. Recently, researchers have emphasized genome-wide association studies. Results of two genome-wide association studies on panic disorder failed to show significant associations. Evidence exists for differences regarding gender and ethnicity in panic disorder. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions, and pharmacogenetic studies are needed. [PubMed Citation] [Order full text from Infotrieve]

16) Mitchell VA, Jeong HJ, Drew GM, Vaughan CW
Cholecystokinin exerts an effect via the endocannabinoid system to inhibit GABAergic transmission in midbrain periaqueductal gray.
Neuropsychopharmacology. 2011 Aug;36(9):1801-10.
Cholecystokinin modulates pain and anxiety via its functions within brain regions such as the midbrain periaqueductal gray (PAG). The aim of this study was to examine the cellular actions of cholecystokinin on PAG neurons. Whole-cell patch clamp recordings were made from rat midbrain PAG slices in vitro to examine the postsynaptic effects of cholecystokinin and its effects on synaptic transmission. Sulfated cholecystokinin-(26-33) (CCK-S, 100-300?nM), but not non-sulfated cholecystokinin-(26-33) (CCK-NS, 100-300?nM) produced an inward current in a sub-population of opioid sensitive and insensitive PAG neurons, which did not reverse over a range of membrane potentials. The CCK-S-induced current was abolished by the CCK1 selective antagonist devazepide (100?nM), but not by the CCK2 selective antagonists CI988 (100?nM, 1??M) and LY225910 (1??M). CCK-S, but not CCK-NS produced a reduction in the amplitude of evoked GABA(A)-mediated inhibitory postsynaptic currents (IPSCs) and an increase in the evoked IPSC paired-pulse ratio. By contrast, CCK-S had little effect on the rate and amplitude of TTX-resistant miniature IPSCs under basal conditions and when external K(+) was elevated. The CCK-S-induced inhibition of evoked IPSCs was abolished by the cannabinoid CB1 receptor antagonist AM251 (3??M), the mGluR5 antagonist MPEP (10??M) and the 1, 2-diacylglycerol lipase (DAGL?) inhibitor tetrahydrolipstatin (10??M). In addition, CCK-S produced an increase in the rate of spontaneous non-NMDA-mediated, TTX-dependent excitatory postsynaptic currents (EPSCs). These results suggest that cholecystokinin produces direct neuronal depolarisation via CCK1 receptors and inhibits GABAergic synaptic transmission via action potential-dependent release of glutamate and mGluR5-induced endocannabinoid signaling. Thus, cholecystokinin has cellular actions within the PAG that can both oppose and reinforce opioid and cannabinoid modulation of pain and anxiety within this brain structure. [PubMed Citation] [Order full text from Infotrieve]

17) Kolik LG
[Experimental study of antidepressant effects of GB-115 dipeptide].
Eksp Klin Farmakol. 2011;74(1):3-5.
It was previously reported that GB-115 [Ph(CH2)5CO-Gly-D-Trp-NH2], a tryptophan-containing dipeptide analog of endogenous CCK4, exhibited pronounced anxiolytic effects in behavioral models of anxiety targeted on the "passive" phenotype of the emotional stress reaction. The aim of the present work was to study the modulator action of GB-115 (0.0125-0.1 mg/kg, i.p.) on emotional processes in both mongrel and inbred (BALB/c and C57B1/6) mice with opposite emotionality in Porsolt's test. GB-115 injected at a dose of 0.025 mg/kg led to a decrease in the immobilization time in all animals tested. The effect observed was less potent than that of amitriptyline (10 mg/kg). In contrast to the case of BALB/c mice, GB-115 increased the latent period in both C57B1/6 mice with active type of behavior and in mongrel mice. There were no changes in spontaneous locomotor activity after the acute administration of GB-115 in inbred and mongrel mice. It was found that GB-115 at an anxiolytic dose produced antidepressant-like effects independently of the genetically controlled emotional stress reaction phenotype. These results indicate that the novel dipeptide analog of CCK4 may have potential in the clinical management of concurrent anxiety and depression. [PubMed Citation] [Order full text from Infotrieve]

18) Hwang YS, Shim I, Chang JW
Anxiety responses and neurochemical changes in a kaolin-induced rat model of hydrocephalus.
J Neurosurg Pediatr. 2011 Apr;7(4):401-7.
[PubMed Citation] [Order full text from Infotrieve]

19) Steckler T
Developing small molecule nonpeptidergic drugs for the treatment of anxiety disorders: is the challenge still ahead?
Curr Top Behav Neurosci. 2010;2:415-28.
Neuropeptide systems have been considered a major opportunity for the development of novel treatment approaches for anxiety disorders based on preclinical evidence and neurochemical alterations seen in anxiety disorders. This excitement was further facilitated by the fact that drugs acting at these systems, such as CRF1 antagonists, NK1 antagonists, NK3 antagonists or CCK2 antagonists, may have unique properties not seen with drugs affecting more classical mechanisms involved in anxiety. Consequently, there have been major efforts to develop such small-molecule, nonpeptide receptor ligands. A number of these molecules have been tested in the clinic, either in trials where levels of anxiety served as a secondary measure, or in a few studies with patients suffering from anxiety disorders. But unfortunately, and despite all the efforts of the field as a whole, we still lack convincing clinical proof-of-concept for any of the neuropeptidergic approaches in patients. It must, therefore, be concluded that neuropeptide targets remain a promising approach for the development of the next generation drugs to treat anxiety disorders, but that they continue to be high-risk targets for drug development. [PubMed Citation] [Order full text from Infotrieve]

20) Wang H, Spiess J, Wong PT, Zhu YZ
Blockade of CRF1 and CCK2 receptors attenuated the elevated anxiety-like behavior induced by immobilization stress.
Pharmacol Biochem Behav. 2011 May;98(3):362-8.
Two highly co-localized neurotransmitters: corticotropin-releasing factor (CRF) and cholecystokinin (CCK), have been implicated in the development of stress-related anxiety disorders. This study was designed to examine the role of CRF1 and CCK2 receptors on the anxiety-like behavior induced by immobilization stress. Our results showed that 30-min immobilization enhanced the anxiety-like behavior in C57BL/6J mice examined in the elevated plus maze (EPM). The combined pretreatment of CR2945 (a CCK2 receptor antagonist) and antalarmin (a CRF1 receptor antagonist) fully blocked this elevated anxiety-like behavior, while the application of CR2945 or antalarmin alone showed only partial effects. The increased expression of CRF1 and CCK2 receptors at protein levels in three anxiety-related brain regions: cortex, hippocampus and hypothalamus, was detected by Western blot. The increased mRNA expression of CCK, CRF, CCK2 and CRF1 receptors was also examined by real-time RT-PCR. Our study demonstrated that the blockade of CRF1 and CCK2 receptors attenuated the elevated anxiety-like behavior induced by immobilization stress, suggestive of the CRF and CCK systems contributing to the development of stress-related anxiety behavior. [PubMed Citation] [Order full text from Infotrieve]