Previous work on this project demonstrated that Phencyclidine (PCP): (1) has a biphasic dose response curve with respect to dopamine (DA) release, and (2) uncouples the cholinergic system in the caudate nucleus, an effect that is probably secondary to the DA response, and (3) that behaviorally active metabolites have no effect on the cholinergic system, but do effect DA efflux. On the basis of these neurochemical and behavioral findings, we are hypothesizing that PCP has two effects on the presynaptic DA terminal and that the two responses are the result of two different actions of PCP. One effect is specific (at low doses of PCP) releasing DA and the second, non-specific (at high doses) inhibiting release of DA. In this proposal, we will attempt to separate the biphasic effects of PCP using congeners which have been demonstrated to bind to PCP receptors and to elicit PCP-like behavior. We are proposing to use Ketamine (KET) and N-ethylphenylcyclohexylamine (PCE) as PCP agonists to separate the increase and decrease in DA efflux by PCP. PCE has a higher affinity for the receptor, whereas KET has low binding properties. The dose response of these PCP congeners will be examined in neurochemical, behavioral and voltammetric protocols in an effort to separate the two DA efflux responses. If this biphasic response is resolvable into two components, each component can be characterized pharmacologically in terms of agonist and antagonist. The protocols that would be developed from this study could then be used to evaluate potential antagonists, from which a specific antagonist could be identified and synthesized. The project is divided into four components: 1) separating the biphasic response of DA efflux to PCP; 2 and 3) Characterizing the biphasic effect with pharmacological antagonists, selected on the basis of their site action on the DA neuron; D) determining the effect of prenatal exposure to PCP on postnatal neurochemical development.
