Subpopulations of dopamine (DA)-containing neurons within the A9 and A10 regions of the midbrain contain the peptide cholecysto-kinin (CCK). Intravenously and microiontophoretically administered CCK potently excites a subpopulation of DA cells that may correspond to those cells which also contain CCK. In addition to this transient excitation, CCK exerts a more enduring modulatory effect on DA neurons with regard to their sensitivity to the inhibitory effects of intravenous apomorphine and microiontophoretic DA. Preliminary studies have shown that the excitatory and modulatory effects of CCK can also occur independently and that distinct DA pathways originating in the midbrain appear to be differentially affected by intravenous CCK. Given the relevance of midbrain DA systems to our current hypotheses regarding the neurobiology of several neurological and psychiatric disorders, a series of studies are proposed to begin to explore in more detail the interactions of CCK with identified DA neuronal subpopulations. In general, advancements in the field of CCK research have been hindered by the lack of specific and potent antagonists. Several new CCK antagonists with high affinity for central and/or peripheral CCK receptors have been developed. In the present proposal, these compounds will be employed to investigate the receptor specificity of the electrophysiological effects of CCK on identified subpopulations of DA neurons. In addition, the direct and modulatory electrophysiological effects of CCK on striatal neurons will be characterized and compared to the effects of stimulation of striatal CCK afferents. It is hoped that the information obtained from these studies will lead to a better understanding of the physiology of distinct midbrain DA neuronal pathways. This knowledge, combined with that obtained with anatomical and biochemical techniques, may aid in the formulation of testable hypotheses concerning the etiology of disorders linked to central DA neuronal dysfunction.
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