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]