PCP AND MIDBRAIN DOPAMINE NEURONS: CELLULAR NEUROBIOLOGY

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.