This is a proposal to continue our studies of the behavioral pharmacology of phencyclidine (PCP) in laboratory animals. PCP abuse remains a serious public health problem requiring a better understanding of its behavioral effects relevant to this abuse. In addition, rapid advances being made in our understanding of the cellular bases for these effects also promise to provide important information about brain-behavior relationships. Previous research has shown that PCP shares many biochemical and behavioral properties with drugs from other chemical classes, including, psychotomimetic opioids such as cyclazocine, (+)-N- allylnormetazocine and dextrorphan. We have also identified others drugs with PCP-like effects such as etoxadrol, dexoxadrol and MK-801. We propose to continue our studies of these PCP- like drugs by studying their discriminative stimulus properties (a model for human subjective effects) in rats and monkeys. An extensive study of structural requirements of opioids for PCP-like effects will facilitate an understanding of receptor-mediation for these effects. We also propose to compare the effects of PCP and these PCP-like drugs in other behavioral procedures to determine the extent of the overlap in their effects and to address the question whether the PCP receptor may be involved in these effects and whether specificity of action can be obtained. Procedures to be used include i.v. drug self-administration, an animal model of anxiolytic effects, interactions with CNS- depressant drugs and cross dependence studies. We will follow up our findings of dependence upon PCP with additional studies to determine the role of dependence in PCP self-administration. Finally, a major new direction for the project is to investigate the role of excitatory amino acid neurotransmission in the behavioral actions of PCP by evaluating the hypothesis that PCP has opposing actions to N-methyl-d-aspartate. These studies may lead to the identification of therapeutic uses of PCP-like drugs.
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