Fink H, Rex A, Voits M, Voigt JP.
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
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]
GR, Raymond R, DeSousa NJ, Nobrega JN, Vaccarino FJ.
CCK(B) receptor binding in rat amygdala in animals demonstrating greater anxiety-like
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."
Chrystel, Thiebot, Marie-Helene, Touitou, Yvan, Hamon, Michel, Cesselin, Francois,
Enhanced Cortical Extracellular Levels of
Cholecystokinin-Like Material in a Model of Anticipation of Social Defeat in the
J. Neurosci. 2001 21: 262-269
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
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.
(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]
D, Ahlin A, Svanborg P, Lindefors N.
Pentagastrin test for anxiety--psychophysiology
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]
H, Whang WW, Kim HT, Pyun KH, Cho SY, Hahm DH, Lee HJ, Shim I.
of neuropeptide Y and cholecystokinin in the rat brain by chronic mild stress.
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]
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]
[Behavioral and neurochemical study on the role of the brain
cholecystokinin system in anxiety]
Hokkaido Igaku Zasshi
"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]
TV, Nielsen FC.
Regulation of neuronal cholecystokinin gene transcription.
Scand J Clin Lab Invest Suppl 2001;(234):61-7
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.
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]
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.
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."
K, King N, Poonai N, Seeman P, Ulpian C, Kennedy J.
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]
H, Stiller CO, Brodin E.
Peripheral axotomy increases cholecystokinin
release in the rat anterior cingulate cortex.
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]
TV, Rehfeld JF, Nielsen FC.
Function of the C-36 to T polymorphism
in the human cholecystokinin gene promoter.
"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."
MA, Courteix C, Boucher M, Meen M, Fialip J, Eschalier A, Ardid D.
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
A, Holsboer F, Rupprecht R.
Increased ACTH concentrations associated
with cholecystokinin tetrapeptide-induced panic attacks in patients with panic
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]
J, Zhou Y, Koszycki D, Vaccarino FJ, Bradwejn J.
Effects of CCK-4
infusion on the acoustic eye-blink startle and psychophysiological measures in
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]
T, Akiyoshi J, Isogawa K, Kohno Y, Hikichi T, Nagayama H.
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]
JL, Liberzon I.
Dose response of adrenocorticotropin and cortisol
to the CCK-B agonist pentagastrin.
"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]
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.
"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]
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]
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]
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
"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]
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
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.
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]
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.
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
Modulation of memory, reinforcement and anxiety parameters
by intra-amygdala injection of cholecystokinin-fragments Boc-CCK-4 and CCK-8s.
"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]
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]
A, Marsden CA, Fink H.
Cortical 5-HT-CCK interactions and anxiety-related
behaviour of guinea-pigs: a microdialysis study.
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]
V, Harro J, Allikmets L.
The effect of drugs acting on CCK receptors
and rat free exploration in the exploration box.
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.
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.
"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."
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]
S, Vaccarino FJ.
Cholecystokinin receptor subtypes: role in the modulation
of anxiety-related and reward-related behaviours in animal models.
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
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]
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]
J, Oreland L, Vasar E, Bradwejn J.
Impaired exploratory behaviour
after DSP-4 treatment in rats: implications for the increased anxiety after noradrenergic
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]
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
(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]
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.
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.
and anxiety in normal volunteers: an investigation of the anxiogenic properties
of pentagastrin and reversal by the cholecystokinin receptor subtype B antagonist
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]
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.
"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]
M, McCort-Tranchepain I, Ducos B, Roques BP, Durieux C.
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."
Belcheva I, Belcheva S, Petkov VV, Petkov VD.
in behavioral responses to cholecystokinin microinjected into rat nucleus accumbens
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."
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]
CF, Guimaraes FS.
Anxiogenic effect of cholecystokinin in the dorsal
Neuropsychopharmacology. 2004 Jan;29(1):101-7.
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
H, Chandler S, Beitz AJ, Shipley MT, Behbehani MM.
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]
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]
UD, Slate SO, Geraci M, Uhde TW.
Peptides and anxiety: a dose-response
evaluation of pentagastrin in healthy volunteers.
"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]
S, Bednar I, Qureshi GA, Sodersten P.
Brain cholecystokinin tetrapeptide
levels are increased in a rat model of anxiety.
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]
J, Koszycki D, Annable L, Couetoux du Tertre A, Reines S, Karkanias C.
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.
sensitivity to cholecystokinin tetrapeptide in panic disorder. Clinical and behavioral
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]
B, Domeney AM, Hughes J, Kelly ME, Naylor RJ, Woodruff GN.
effects of CCK-B antagonists.
Neuropeptides 1991 Jul;19
"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."
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."
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]
Cholecystokinin in psychiatric
research: a time for cautious excitement.
J Psychiatr Res
"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]
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]
JL, Young EA.
Hypothalamic-pituitary adrenal response to cholecystokinin-B
receptor agonism is resistant to cortisol feedback inhibition.
"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."
AM, Aguilar-Roblero R, Perez De La Mora M.
Role of cholecystokinin-A
and cholecystokinin-B receptors in anxiety.
"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]
T, Inoue T, Tsuchiya K, Hashimoto S, Ohmori T, Koyama T.
of the selective CCKB receptor antagonist LY288513 on conditioned fear stress
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]
M, Yassouridis A, Hua Y, Wendrich M, Naber D, Wiedemann K.
dissociation affects the behavioral response to cholecystokinin tetrapeptide in
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]
MA, Duffin J, Shlik J, Bradwejn J.
The ventilatory response to cholecystokinin
tetrapeptide in healthy volunteers.
"We conclude that CCK-4 does not act to induce
panic by altering the central (CO(2) sensitive) chemoreceptor." [Abstract]
RA, Rud'ko OI, Korotkova TM, Obukhova MF, Ashmarin IP.
of immunization against cholecystokinin fragment 30-33 in the behavior of white
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]
P, Eser D, Aicher S, Schule C, Baghai TC, Padberg F, Ella R, Moller HJ, Rupprecht
Effects of alprazolam on cholecystokinin-tetrapeptide-induced
panic and hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study.
2003 May;28(5):979-84. Epub 2003 Mar 26.
(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]
P, Baghai TC, Schuele C, Strohle A, Padberg F, Kathmann N, Schwarz M, Moller HJ,
Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4)
induced panic in healthy volunteers.
2001 Nov;25(5):699-703 [Abstract]
P, Eser D, Padberg F, Baghai TC, Schule C, Rotzer F, Ella R, Moller HJ, Rupprecht
Effects of tiagabine on cholecystokinin-tetrapeptide (CCK-4)-induced
anxiety in healthy volunteers.
Depress Anxiety. 2003;18(3):140-3.
Raud S, Runkorg K, Veraksits A, Reimets A, Nelovkov
A, Abramov U, Matsui T, Bourin M, Volke V, Koks S, Vasar E.
mutation of CCK2 receptor gene modifies the behavioural effects of diazepam in
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]
A, Romeo E, di Michele F, Pasini A, Hermann B, Gajewsky G, Holsboer F, Rupprecht
Induced panic attacks shift gamma-aminobutyric acid type A receptor
modulatory neuroactive steroid composition in patients with panic disorder: preliminary
Arch Gen Psychiatry. 2003 Feb;60(2):161-8.
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
Neurochem Int. 2003 Jan;42(1):87-92.
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]
V, Sebret A, Beslot F, Matsui T, Roques BP.
Behavioral profile of
CCK2 receptor-deficient mice.
"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]
A, Rodi D, Cavallini S, Marino S, Beani L, Bianchi C.
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
M, Bado A, Dauge V.
Leptin decreases feeding and exploratory behaviour
via interactions with CCK(1) receptors in the rat.
"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]
JL, Le Melledo J, Bichet DG.
Dose response of arginine vasopressin
to the CCK-B agonist pentagastrin.
"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
N, Sharp T.
Neuroanatomical targets of anxiogenic drugs in the hindbrain
as revealed by Fos immunocytochemistry.
"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]
S, Mannisto PT, Bourin M, Shlik J, Vasar V, Vasar E.
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]
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.
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."
S, Soosaar A, Voikar V, Bourin M, Vasar E.
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]
TD Jr, Ekhator NN, Nicholson WE, Arndt S, Loosen PT, Orth DN.
and inter-individual correlations between cholecystokinin and corticotropin-releasing
hormone concentrations in human cerebrospinal fluid.
"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]
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]
BB, Rady JJ, Smith DJ, Fujimoto JM.
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]
I, Boulenger JP, Bradwejn J, Lavallee YJ, Jolicoeur FB.
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]
M, Shlik J, Kennedy SH, Vaccarino FJ, Houle S, Bradwejn J.
correlates of CCK-4-induced panic attacks in healthy humans: a comparison of two
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]
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."
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]
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]
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]
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]
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]
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]
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
"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]
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.
"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."
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
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."
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]
S. Kopin, Edward W. McBride, Michelle C. Gordon, Suzanne M. Quinn, and Martin
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
Benedetti F, Amanzio M, Casadio C, Oliaro
A, Maggi G.
Blockade of nocebo hyperalgesia by the cholecystokinin
Pain 1997 Jun;71(2):135-40
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.
of placebo analgesia: from endogenous opioids to cholecystokinin.
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.
the cholecystokinin agonist pentagastrin in patients with generalized anxiety
Am J Psychiatry 1997 May;154(5):700-2
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]
R, Rudolf S, Molle M, Fehm HL, Born J.
on selective attention depend on level of activation.
"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."
LD, Beart PM, Horne MK, Finkelstein DI, Carrive P, Paxinos G.
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]
F, Martin JR, Moreau JL.
Behavioral effects of CCKB receptor ligands
in a validated simulation of panic anxiety in rats.
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)
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]
SA, Frankland PW, Petrisano S, Bush DE, Yeomans JS, Vaccarino FJ.
CCKB antagonist, L-365,260, attenuates fear-potentiated startle.
"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.
enhances the acoustic startle response in rats.
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]
JA, Brett RR.
The benzodiazepine receptor inverse agonist FG 7142
induces cholecystokinin gene expression in rat brain.
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]
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
J, Wahlstrom G, Oreland L.
Cholecystokinin receptor binding after
long-term ethanol treatment in rats.
Alcohol Alcohol 1994
"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]
JL, Nesse RM.
Pentagastrin infusions in patients with panic disorder.
I. Symptoms and cardiovascular responses.
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]
E, Lang A, Harro J, Bourin M, Bradwejn J.
Evidence for potentiation
by CCK antagonists of the effect of cholecystokinin octapeptide in the elevated
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]
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]
XJ, Hao JX, Seiger A, Hughes J, Hokfelt T, Wiesenfeld-Hallin Z.
pain-related behaviors in spinally injured rats: evidence for functional alterations
of the endogenous cholecystokinin and opioid systems.
"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]
E, Peuranen E, Harro J, Lang A, Oreland L, Mannisto PT.
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
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."
J, Marcusson J, Oreland L.
Alterations in brain cholecystokinin
receptors in suicide victims.
"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.
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]
M, Yassouridis A, Hua Y, Wendrich M, Jahn H, Wiedemann K.
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
A, Kellner M, Holsboer F, Wiedemann K.
Anxiolytic activity of atrial
natriuretic peptide in patients with panic disorder.
J Psychiatry 2001 Sep;158(9):1514-6 [Abstract]
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]
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]