The drug of abuse, phencyclidine (PCP), has profound effects on dopaminergic (DA) neuronal systems which originate in the midbrain. These systems have been implicated in many of the behavioral effects of PCP as well as its reinforcing properties and abuse potential. PCP is will known to block Da reuptake and enhance DA release. In addition to indirect DA agonist action, PCP acts as a non-competitive antagonist of the excitatory amino acid N-methyl-d-aspartate at a site designated the """"""""PCP receptor,"""""""" and also interacts with haloperidol-sensitive sigma binding sites (""""""""sigma receptors""""""""). PCP has complex effects on the electrophysiological activity of nigrostriatal (NS) and mesoaccumbens (MA) DA cells. These effects are not due solely to the indirect DA agonist properties of PCP. It is likely that actions of PCP at PCP and/or sigma receptors contribute significantly to its overall effects on DA cell physiology. The multiple actions of the drug, however, have precluded clear assessments of the contributions the separate receptors make to the overall effects of PCP on DA cell activity. The recent availability of compounds which are selective for the PCP and sigma sites has provided tools which are required to begin to examine in greater detail the mechanism of action of PCP on the basal physiology and pharmacology of DA neurons. The proposed in vivo and in vitro studies will employ extracellular single-unit recording techniques in an evaluation of the effects of PCP receptor and sigma receptor ligands onrat DA cell activity. These studies will also look into possible sites of action for the effects of these drugs on DA cell activity. The in vivo studies will examine antidromically identified NSDA and MADA cell subpopulations. The abuse of PCP often involves repeated use os the drug. This might be expected to result in changes in the autoregulatory capacity of DA cells due to prolonged indirect stimulation of DA receptors. Thus, the effects of repeated administration of PCP on the responsiveness of impulse- regulating somatodendritic DA autoreceptors will be determined. It is hoped that these studies will lead to a better understanding of the acute and chronic effects of PCP on midbrain DA neurons.
