The goal of the proposed research remains the elucidation of the neurobiological mechanisms underlying the abuse-promoting and psychotomimetic effects of phencyclidine (PCP) and related drugs. During the previous project periods, we identified specific PCP receptors in brain membranes and identified them as the sites at which PCP-like drugs exert their unique actions. We shall now apply those findings to the determination of the neuroanatomical and functional relationship of the PCP receptor to other transmitter and peptide receptor systems, and to the characterization of the PCP receptor at the molecular level. The functional localization of PCP receptor with respect to dopaminergic, serotonergic and intrinsic striatal neurons will be revealed by quantitative PCP-receptor autoradiography in control animals and following selective neurotoxic lesions. PCP-like drugs have been implicated as functional antagonists of NMDA excitatory amino acid receptors. We shall determine the competitive, noncompetitive or allosteric biochemical mechanism of that interaction, and whether PCP and NMDA receptors are co-localized in hippocampus, the brain area in which both receptors have their highest densities. The specific neurochemical effects of chronic PCP administration upon PCP and neurotensin (NT) receptors and on NT levels will be determined in order to elucidate the mechanisms involved in chronic PCP abuse. The endogenous brain neuropeptide with PCP-like pharmacological activity which we identified during the previous project period will be isolated and purified. To clarify the molecular basis of PCP actions, we shall purify and characterize the receptor protein which we have solubilized, and shall characterize cultured NCB20 neuroblastoma-brain hybrid cells, which possess specific PCP binding sites, as a potential model system for molecular studies of PCP receptors. Specific PCP binding sites have been reported on human lymphocyte membranes. We shall determine whether those sites are pharmacologically similar to and coordinately regulated with brain PCP receptors. If so, we shall determine whether lymphacyta PCP binding sites constitute biological markers of brain PCP receptor function in living organisms. The results of these studies will contribute towards the understanding and treatment of important drug-abuse and mental health problems.
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