The proposed research will continue to investigate the neurochemical pharmacology of phencyclidine (PCP) in the rat. In order to determine the potential behavioral significance of our observations we will compare the effects of drugs within several distinct classes which either have or do not have PCP-like behavioral properties. We propose to continue our studies on the effects of a variety of drugs from several classes on turning behavior in rats with unilateral destruction of the nigrostriatal dopaminergic pathway. Our preliminary data suggests that turning behavior may be elicited via an action on the PCP/sigma receptor. Our most recent work shows that drugs like cyclazocine which are PCP-like in the turning model, do not directly elicit significant dopamine (DA) release or inhibit DA reuptake in striatal tissue. This suggest the involvement of non-striatal dopaminergic mechanisms and/or non-dopaminergic striatal mechanisms in turning behavior. We have recently determined that PCP-like drugs may elicit turning behavior via an interaction with glutamate receptors on cholinergic striatal neurons. Since glutamate receptors are known to mediate an excitatory effect on many neurotransmitter systems in many areas of the brain including those related to turning behavior, we propose to investigate the effect of PCP and related drugs on the interaction between dopaminergic, cholinergic, and glutamatergic systems in the substantia nigra, nucleus accumbens, and striatum. We propose to extensively characterize the glutamate receptor subtype(s) on which PCP is acting and to determine whether this effect occurs at the recognition site, at the ionic conductance site which is regulated by glutamate, or at some distal site. We will also determine whether this effect of PCP on ACh release occurs in brain areas other than the striatum and whether PCP-like drugs block the effect of glutamate-induced release of other neurotransmitters (primarily DA and glutamate itself). We also propose to extend the investigation of these mechanisms to brain areas believed to play a role in the effect that PCP has on emotionality (prefrontal cortex) and memory (hippocampus).
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