The effects of phencyclidine (PCP) on catecholaminergic neuronal pathways in the mammalian central nervous system function will be studied using extracellular electrophysiological recordings from single neurons and using in vivo electrochemistry to measure catecholamine transmitter release in vivo. We will apply drugs locally in situ and to isolated neuronal circuits transplanted in oculo by microiontrophoresis and by pressure ejection form multibarrel micropipettes. Drugs will also be applied by superfusion and by eyedrops to the intraocular brain grafts, and i.p. to the whole animal. We have characterized catecholomimetic PCP effects in the cerebellar cortex, hippocampus and prefrontal cortex electrophysiologically, and we have studied PCP effects on dopamine release in the caudate nucleus. We will electrophysiologically characterize PCP interactions with norepinephrine synapses in the prefrontal cortex and with dopamine in the accumbens. We will also investigate PCP interactions with kappa and sigma agonists, we will study changes in PCP effects with chronic exposure, and we will investigate if PCP interactions with dopamine synapses are altered in animals that self-administer PCP. Finally we will determine if the PCP effects observed in rat models are similarly produced in human brain xenographs in oculo in rats. A greater understanding of how ethanol alters CNS function should furnish new insights into the problems of PCP abuse and could lead to pharmacological approaches to eliminate the unwanted effects of this psychotomimetic drug without changing its beneficial qualities.
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