Jacques Bradwejn

Cholecystokinin and psychiatric disorders : role in aetiology and potential of receptor antagonists in therapy.

SummaryCholecystokinin (CCK) is one of the most abundant neuropeptides in the brain. It is found in the highest levels in cortical and limbic structures and also in the basal ganglia. Two subtypes of CCK receptors have been described in the brain and gastrointestinal tissues. CCKA (alimentary subtype) receptors are mainly located in the gastrointestinal tract, regulating secretion of enzymes from the pancreas and emptying of the gallbladder. However, CCKA receptors are also found in several brain regions, with the highest densities in structures poorly protected by the haematoencephalic barrier (the area postrema, nucleus tractus solitarius and hypothalamus). The distribution of CCKB (brain subtype) receptors overlaps with the localisation of CCK and its mRNA in different brain areas, with the highest densities in the cerebral cortex, basal ganglia, nucleus accumbens and forebrain limbic structures.Both subtype of CCK receptor belong to the guanine nucleotide-binding protein-(G protein)-linked receptor superfamily containing 7 transmembrane domains. Signal transduction at CCK receptors is mediated via Gq protein-related activation of phospholipase C and the formation of inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). Recent cloning of CCKA and CCKB receptors has shown that mRNA for both receptors is distributed in the same tissues as established in radioligand binding and receptor autoradiography studies, with few exceptions.The existence of multiple CCK receptors has fuelled the development of selective CCKA and CCKB receptor antagonists. These antagonists belong to distinct chemical groups, including dibutyryl derivatives of cyclic nucleotides, amino acid derivatives, partial sequences and derivatives of the -COOH terminal sequence heptapeptides of CCK, benzodiazepine derivatives, ‘peptoids’ based on fragments of the CCK molecule, and pyrazolidinones. At the present time, the compounds of choice for blockade of the CCKA receptor are lorglumide, devazepide and lintitript (SR27897). L-365,260, CI-988, L-740,093 and LY288513 are the drugs most widely used to block CCKB receptors.Studies with CCK antagonists (and agonists) in animals and humans suggest a role for CCK in the regulation of anxiety and panic. The administration of CCK agonists [ceruletide (caerulein), CCK-4, pentagastrin] has an anxiogenic action in various animal models and in different animal species. However, the anxiogenic action of CCK agonists is restricted to nonconditioned (ethological) models of anxiety, with very limited activity in the ‘classical’ conditioned models. Pharmacological studies have revealed that CCKB receptors are the key targets in the anxiogenic action of CCK agonists. Nevertheless, CCKB antagonists displayed very little activity, if any at all, in these models, but strongly antagonised the effects of CCKB agonists. The anxiogenic/panicogenic action of CCKB agonists (CCK-4, pentagastrin) is even more pronounced in human studies, but the effectiveness of CCKB antagonists as anxiolytics remains unclear. Clinical trials performed to date have provided inconclusive data about the anxiolytic potential of CCKB receptor antagonists, probably because of limiting pharmacokinetic factors.The results of some animal experiments suggest a role for CCK in depression. The administration of CCKB antagonists causes antidepressant-like action in mouse models of depression. However, human studies replicating this result have yet to be carried out.A prominent biochemical alteration in schizophrenia is a reduction of CCK levels in the cerebral cortex. This change may be related to the loss of cortical neurons, due to the schizophrenic process itself. In animal studies (mainly in mice), administration of CCK agonists and antagonists has been shown to be effective in several models, reflecting a possible antipsychotic activity of these drugs. However, the data obtained in human studies suggest that CCK agonists and antagonists do not improve the symptoms of schizophrenia. Taking into account the reduced levels of CCK and its receptors found in schizophrenia, treatments increasing, but not blocking, brain CCK activity may be more appropriate.

Sensitivity to CCK-4 in Women with and without Premenstrual Dysphoric Disorder (PMDD) During Their Follicular and Luteal Phases

The authors determined whether women with premenstrual dysphoric disorder (PMDD) exhibit a heightened sensitivity to the panicogenic effects of CCK-4 administration and whether this enhanced sensitivity to CCK-4 would vary with the phase of the menstrual cycle at the time of CCK-4 injection. Twenty-one normal controls and 18 PMDD women were randomly assigned to receive the first and second CCK-4 injection during the follicular phase and the luteal phase or vice versa. PMDD women showed a greater anxiety and panic response to CCK-4. These preliminary results suggest that the CCK-B system may play a role in the pathophysiology of PMDD.

Acute and Chronic Role of 5-HT3 Neuronal System on Behavioral and Neuroendocrine Changes Induced by Intravenous Cholecystokinin Tetrapeptide Administration in Humans

The influence of single and multiple oral doses of ondansetron, a selective 5-HT3 receptor antagonist, was evaluated against placebo on cholecystokinin tetrapeptide (CCK-4)-induced behavioral and neuroendocrine changes in humans. As compared to placebo, subjects receiving acute ondansetron treatment showed a significant decrease in the sum intensity of CCK-4-induced-panic symptoms (iPSS). Pre-CCK-4 neuropeptide Y (NPY) plasma levels were significantly higher and maximal changes in cortisol, growth hormone, and prolactin secretion from baseline (Δmax) were significantly lower in the ondansetron group. After ondansetron and placebo chronic administration, there were no statistical differences in the iPSS between groups. Pre-CCK-4 NPY plasma levels were significantly higher; whereas, Δmax for NPY significantly lower in the ondansetron group as compared to placebo. These results suggest a role for the 5-HT3 receptor in the neurobiology of panic disorder through a possible interaction with CCK and NPY systems. Ondansetron chronic effect on CCK-4-induced behavioral changes needs further exploration.

Emotional and cognitive factors connected with response to cholecystokinin tetrapeptide in healthy volunteers

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.

The role of the β-noradrenergic system in cholecystokinin-tetrapeptide-induced panic symptoms

BACKGROUNDnThe authors determined whether effective beta-adrenergic blockade could attenuate the panicogenic effects of cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers.nnnMETHODSnSubjects were randomly assigned to either a propranolol (n = 14) or placebo (n = 16) infusion. Ten minutes after completion of the infusion subjects received a bolus injection of CCK-4 (50 micrograms).nnnRESULTSnAcute pretreatment with propranolol was more effective than placebo in decreasing behavioral and cardiovascular sensitivity.nnnCONCLUSIONSnThese preliminary results suggest that the panicogenic effects of CCK-4 are mediated, in part, through the beta-adrenergic system.

The effect of cholecystokinin tetrapeptide on respiratory resistance in healthy volunteers

The effects of cholecystokinin tetrapeptide (CCK-4) on respiratory resistance were studied in 14 healthy volunteers by the registration of slow vital capacity and flow volume loop during forced respiration test. The administration of CCK-4 (50 micrograms) was performed in a double-blind and placebo-controlled design. Injections of CCK-4 induced prominent and time-limited paniclike symptoms in all healthy volunteers. Four volunteers (29%) experienced a panic attack. Subjective dyspnea was experienced by the majority of subjects at the peak of CCK-4 effect and seemed related to a diminution in vital capacity parameters; however, the forced respiration test did not reveal bronchoconstriction after CCK-4 challenge. Administration of CCK-4 also induced a short-lasting increase in heart rate and skin blood flow. This study suggests that dyspnea induced by CCK-4 is not related to changes in respiratory resistance.

DEVELOPMENT OF A SENSITIVE AND SPECIFIC ASSAY SYSTEM FOR CHOLECYSTOKININ TETRAPEPTIDE

Cholecystokinin is a gastrointestinal and neuropeptide which has been implicated in a wide range of physiological and behavioral processes. We have developed a sensitive and specific assay system to measure the various forms of cholecystokinin (CCK) in human plasma. This 3-step system involves i) extraction of CCK fragments from plasma using reverse phase chromatography; ii) separation of peptides by high performance liquid chromatography; and iii) detection and quantification of peptides with a double-antibody radioimmunoassay, using an antibody raised against cholecystokinin tetrapeptide (CCK-4) coupled to thyroglobulin and 125I Bolton-Hunter CCK-4 as tracer. The antibody detects CCK-4, sulfated CCK-8 (CCK-8S) and nonsulfated CCK-8 (CCK-8ns) with equal affinity. The lower limit of detection is 2.7 fmol, with an ED50 of 10.6 +/- 2.2 fmol. Mean CCK-like immunoreactivity (CCK-LI) in the plasma of 12 healthy subjects was determined to be 12.9 +/- 2.1 pM CCK-4 equivalents. Concentrations of each individual peptide in plasma were determined to be 1.0 +/- 0.2 pM, 3.4 +/- 0.8 pM and 1.9 +/- 0.4 pM for CCK-4, CCK-8s and CCK-8ns respectively.