The presence of specific high-affinity binding sites for phencyclidine (PCP) in brain and the fact that PCP can produce in man profound behavioral changes often resembling a schizophrenic psychosis requires that substantial efforts be made to determine the effects of PCP on central nervous system processes. The overall goal of the studies described in this proposal is to examine the action of phencyclidine and a recently isolated PCP-like brain peptide on normal neurobiological processes within the rat central nervous system. Specifically, dopamine cell bodies (A10) in the ventral tegmental area and the mesolimbic-mesocortical areas innervated by those DA neurons have been chosen for study. These pathways have been strongly implicated as anatomical and biochemical substrates likely to be involved in schizophrenia. Using electrophysiological methods of extracellular unit recording, microiontophoretic-micropressure administration, and electrical stimulation of selected pathways to identifiable target cells, PCP and the PCP-like peptide will be studied and compared for their selective actions on specific sites and chemical modes of synaptic transmission. Pharmacological manipulations and selective lesioning techniques will be used to discriminate between a preferential presynaptic or postsynaptic site of action as well as to characterize interactions of the test compounds with dopaminergic and noradrenergic systems. Finally, we will determine if PCP and PCP-like peptide neuronal effects differ between naive animals and those chronically treated with systemically administered PCP. The projects outlined here should enable us to characterize the sites, mechanisms and functional consequences of PCP and PCP-like peptide action on selected neuronal pathways. The resulting data will provide essential information concerning PCP's unique pharmacology. In turn, such findings may be useful for the understanding of specific chemical processes involved in the etiology of schizophrenia.
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