CHOLECYSTOKININ AND PSYCHIATRIC-DISORDERS - ROLE IN ETIOLOGY AND POTENTIAL OF RECEPTOR ANTAGONISTS IN THERAPY

Cholecystokinin (CCK) is one of the most abundant neuropeptides in the brain. It is found in the highest levels in cortical and limbic struc tures and also in the basal ganglia. Two subtypes of CCK receptors hav e been described in the brain and gastrointestinal tissues. CCKA (alim entary subtype) receptors are mainly located in the gastrointestinal t ract, regulating secretion of enzymes from the pancreas and emptying o f the gallbladder. However, CCKA receptors are also found in several b rain regions, with the highest densities in structures poorly protecte d 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 diff erent 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 prot ein (G protein)-linked receptor superfamily containing 7 transmembrane domains. Signal transduction at CCK receptors is mediated via G(q) pr otein-related activation of phospholipase C and the formation of inosi tol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). Recent clon ing of CCKA and CCKB receptors has shown that mRNA for both receptors is distributed in the same tissues as established in radioligand bindi ng and receptor autoradiography studies, with few exceptions. The exis tence of multiple CCK receptors has fuelled the development of selecti ve CCKA and CCKB receptor antagonists. These antagonists belong to dis tinct chemical groups, including dibutyryl derivatives of cyclic nucle otides, amino acid derivatives, partial sequences and derivatives of t he -COOH terminal sequence heptapeptides of CCK, benzodiazepine deriva tives, 'peptoids' based on fragments of the CCK molecule, and pyrazoli dinones. 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 u sed to block CCKB receptors. Studies with CCK antagonists (and agonist s) in animals and humans suggest a role for CCK in the regulation of a nxiety and panic. The administration of CCK agonists [ceruletide (caer ulein), CCK-4, pentagastrin] has an anxiogenic action in various anima l models and in different animal species. However, the anxiogenic acti on of CCK agonists is restricted to nonconditioned (ethological) model s of anxiety, with very limited activity in the 'classical' conditione d models. Pharmacological studies have revealed that CCKB receptors ar e the key targets in the anxiogenic action of CCK agonists. Neverthele ss, 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, pentagastri n) is even more pronounced in human studies, but the effectiveness of CCKB antagonists as anxiolytics remains unclear. Clinical trials perfo rmed to date have provided inconclusive data about the anxiolytic pote ntial of CCKB receptor antagonists, probably because of limiting pharm acokinetic factors. The results of some animal experiments suggest a r ole for CCK in depression. The administration of CCKB antagonists caus es antidepressant-like action in mouse models of depression. However, human studies replicating this result have yet to be carried out. A pr ominent 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 anima l studies (mainly in mice), administration of CCK agonists and antagon ists has been shown to be effective in several models, reflecting a po ssible antipsychotic activity of these drugs. However, the data obtain ed in human studies suggest that CCK agonists and antagonists do not i mprove the symptoms of schizophrenia. Taking into account the reduced levels of CCK and its receptors found in schizophrenia, treatments inc reasing, but not blocking, brain CCK activity may be more appropriate.