This competitive renewal application outlines a broad series of extracellular and intracellular electrophysiological studies which are designed to further the understanding of the basic physiology of different subpopulatons of mesencephalic dopamine-containing neurons. This knowledge would in turn serve as a foundation from which both the effects of acute and repeated exposure to dopamine receptor agonists could be determined. This would allow for the direct testing of possible mechanisms which might account for the observed actions of dopamine receptor agonists on dopamine cells function (such as changes in the pattern of spontaneous activity and responsiveness to pharmacological agents). Specific experiments will examine the influence of excitatory afferent inputs from the pedunculopontine tegmental nucleus and inhibitory serotoneric inputs from the dorsal raphe nucleus on the physiology of dopamine neurons and their response to dopamine receptor agonists. A parallel setof intracellular studies will also be carried out on mesencephalic DA neurons which have bee isolated form adult animals. These studies will together provide a complete characterization of the normal membrane physiology, as well as any changes in this physiology which may occur as a result of dopamine receptor agonist administration. Given the relevance of dopamine agonist-induced psychoses in our current hypotheses regarding the biology of schizophrenia (as well as other disorders), the studies proposed have both a preclinical and clinical importance. Its is hoped that such a detailed investigation of the """"""""basic"""""""" electrophysiological and pharmacological characteristics, together with the examination of mechanisms of dopamine receptor agonist effects on transmembrane ionic currents, will ultimately aid in a better understanding of the etiology of schizophrenia and better therapeutic approaches in its treatment.
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