The overall objective of this research project is to further clarify functional role of cholecystokinin (CCK-8) in the mesolimbic dopamine (DA) system. Existing evidence suggest that the mesolimbocortical DA system is involved in the therapeutic action of antipsychotic drugs (APDs) and the pathophysiology of schizophrenia whereas the mesostriatal DA system is implicated in the extrapyramidal side effects of APDs. DA and CCK-8 are coexisted in a subpopulation of DA neurons in the ventral tegmental area (VTA or A10). It is possible that CCK-8 may be involved in the pathophysiology of schizophrenia and therapeutic actions of APDs. For example, CCK-8 concentration and the number of CCK-8 receptors are lower in some schizophrenic patients, chronic APD treatments increase the number of CCK-8 receptors in limbic and cortical structures and a suspected CCK-8 antagonist (proglumide) reverses the effect produced by chronic APDs and DA neurons in experimental animals. By using the techniques of in vivo electrochemistry, we propose to study the effect of intraventricularly administered CCK-8 on basal DA release in the nucleus accumbens (NAc), a limbic structure which receives topographical CCK/DA projections from the VTA. Basal release of DA will be verified by voltammetric, anatomical and pharmacological methods. In parallel to studying the effects of CCK on DA release, the number of spontaneously active A10 DA cells will be monitored using the technique of extracellular single cell recording. Simultaneous monitoring of these two events in the same preparation will provide a better indication of functional state of the A10 DA system. For comparison, further studies will examine CCK-8 induced changes in basal release of DA in the caudate-putamen (CPu), which receives mesostriatal DA projections. Differences in the action of CCK on these two DA systems will be compared to those obtained from typical and atypical APDs. We will also test newly developed CCK antagonists such as lorglumide and L-364,718 by determining if these compounds can block or reverse CCK- induced changes in basal DA release. These studies are fundamental importance in determining the functional significance of the coexistence of CCK-8/DA in the A10 DA system. Ultimately, such knowledge will help us to understand the pathogenesis of schizophrenia and develop better APDs.
