Cholecystokinin in the central nervous system: Pharmacological characterization, solubilization, and autoradiographic localization of the receptors and interactions with central dopaminergic functions

Abstract

<p>In 1980, cholecystokinin (CCK) was demonstrated to co-exist with dopamine (DA) in certain neurons of the CNS. Since the animal studies were carried out on rodents, little was known about CCK in the brain of higher mammalian species. In the present study, CCK receptors were characterized in the brains of higher mammalian species. The pharmacological characteristics of CCK receptors appear to have been well preserved in the mammalian brain. However, marked differences in the distribution of CCK receptors were observed in several brain areas. There were basically two main types of species-specific differences. The absence or presence of CCK receptors in a given structure and differences in the distribution within a given structure. Although the reasons for such species-specific differences in receptor distribution are not clear at the present time, this evidence cautions against simple extrapolation of data obtained in animal models directly to clinical applications. Moreover, although some animals studies provided evidence of an inhibitory effect of CCK on DA function, which would be compatible with a potential antischizophrenic action, others reported a lack of modulation or an enhancement of DA function. Circling behaviour is commonly used to assess DA function. In the present study, unilateral intracranial microinjections of CCK₈ induced a dose-dependent contraversive circling bias in rats. This CCK₈-induced contraversive circling bias was attenuated by the DA receptor antagonist haloperidol. To further elucidate the mechanism(s) underlying this CCK-induced circling behaviour, the effects of CCK peptides on ligand binding at DA receptors and on DA-stimulated adenylate cyclase were investigated in the rat striatum. Under the assay conditions employed, CCK₈ has no significant acute effects on binding at the DA receptor or on DA-stimulated adenylate cyclase. It is possible that CCK induced its acute facilitatory influence on DA function in the circling behaviour paradigm by altering DA turnover or release. Another problem with the animal studies which were used as the basis for the clinical application was that the vast majority were of an acute nature. In the present study, long-term administration of CCK₈ did not significantly alter DA D₂ receptor densities nor the expression of DA D₂ receptor mRNA. In contrast, long-term haloperidol administrations significantly increased CCK binding in the nucleus accumbens, olfactory tubercle, and frontal cortex. (Abstract shortened by UMI.)</p>