PCP AND MIDBRAIN DOPAMINE NEURONS: CELLULAR NEUROBIOLOGY

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The fact that phencyclidine (PCP) continues to be an abused drug which can produce in man profound alterations in behavior, requires that substantial efforts are crucially necessary to understand its effects on central nervous system function. The overall goal of the studies described in this proposal is to determine the mechanism(s) of action of PCP on normal neurobiological processes within the rat central nervous system. Specifically, the effects of PCP on midbrain dopamine neurons (A10) within the ventral tegmental area (VTA) and the influence of VTA afferents on those cells have been selected for study. As with other drugs of abuse (e.g. cocaine), the A10- dopamine neurons and the mesolimbic-mesocortical structures they innervate have been implicated as anatomical and biochemical substrates likely to be involved in the reinforcing properties of PCP. Also, these same structures are considered underpinnings in the pathophysiology of schizophrenia and, as such, plausibly linked to the psychosis-like effects frequently elicited by PCP. In the present proposal, we will use electrophysiological methods of extracellular recording combined with selective lesions and pharmacological manipulations to determine the transmitter identity contribution to either the intensification or diminishment of PCP's unique excitatory/inhibitory effects on VTA neurons. In addition, intracellular recordings from neurons in the in vitro VTA brain slice preparation will be used to provide an indepth analysis of the effects of acute and chronic PCP on neuronal membrane properties, chemical synapses, and voltage sensitive ion conductances of the neuronal A10 dopamine cells. The projects outlined here should enable us to characterize the consequences of PCP on VTA A10 neurons directly, and the relative contributions made various by afferent inputs to these effects. The data derived from these experiments will provide essential information regarding PCP's unique pharmacological actions on this midbrain dopamine containing system. This in turn may help delineate the neurobiological consequence of phencyclidine abuse, and as such possibly lead to a more rational design of treatments for the various behavioral effects and psychopathologies related to PCP abuse.