The goal of the proposed research remains the elucidation of neurobiological mechanisms underlying mediation of drug-abuse and psychotic states by the phencyclidine (PCP)/NMDA receptor-channel complex. During the initial project period we identified specific PCP receptors in brain membranes and provided biochemical and pharmacological evidence that these sites mediate the unique actions of PCP-related drugs. All PCP-like agents are noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) type of excitatory amino acid receptor; the PCP receptor is situated within the NMDA receptor-gated ion channel. Therefore binding characteristics of ligands to the PCP receptor are sensitive to the state of the ion channel, and elucidation of mechanisms of action of PCP-related drugs requires determination of mechanisms governing regulation of NMDA receptor activation by its agonists, antagonists and modulators. During the previous project period we published evidence from PCP receptor binding studies carried out at equilibrium and by kinetic techniques which support a complex model of the interaction of PCP-related drugs with the NMDA receptor channel. We reported that PCP receptor binding characteristics cannot be explained on the basis of a single affinity component of binding in equilibrium studies or by single exponentials of association/dissociation in kinetic studies, as would be predicted by the """"""""open-channel blocker"""""""" model of PCP action proposed by others. We were able to account for our findings on the basis of a multistate model of NMDA receptor activation in which PCP receptor ligands bind differentially to open and to closed, agonist-associated states of the NMDA channel, and to demonstrate a requirement for multiple molecules of agonist for NMDA channel activation. These techniques now provide us with an analytical tool which will serve as a methodological focus for further elucidation of mechanisms governing NMDA receptor activation and PCP effects in the proposed research. We shall determine the mechanistic basis of the actions of polyamines upon the NMDA/PCP receptor and detect whether their effects are mediated by independent mechanisms or by modulation of the effects of other regulators. The mechanistic basis of the biochemical and functional heterogeneity of NMDA/PCP receptors in cerebellum vs. forebrain will be determined. Acute PCP effects, mediated by the PCP receptor, include induction of a psychotic state in normal subjects closely resembling schizophrenia, and specific exacerbation of illness in schizophrenics. The mechanistic relationship between PCP-induced psychosis and schizophrenia will be determined by studies comparing the detailed characteristics of PCP receptor binding and mechanisms governing NMDA receptor activation in postmortem brain samples derived from schizophrenics vs. matched controls. Together, the proposed studies will significantly advance our understanding of an important mechanism underlying drug abuse and psychiatric illness.
Showing the most recent 10 out of 61 publications
