Phencyclidine (PCP) is a major clinical psychotogenic agent and drug of abuse. PCP and other dissociative anesthetics induce their unique behavioral effects by blocking neurotransmission mediated at the N-methyl-D-aspartate (NMDA)-type glutamate receptor. In addition to the main agonist binding site for glutamate, the NMDA receptor complex contains multiple co-agonist/modulatory sites, including a strychnine-insensitive glycine binding site. In rodents, stimulation of the glycine site reverses PCP-induced hyperactivity, whereas in humans glycine ameliorates PCP psychosis-like symptoms of schizophrenia. In CNS, glycine levels in the immediate vicinity of NMDA receptors are maintained at low, subsaturating doses by the action of colocalized glycine transporters. Therefore, inhibition of glycine uptake, rather than administration of large doses of glycine, may be a preferred method for elevating glycine levels in the immediate vicinity of NMDA receptors. This is an application for continuation of a project initiated in 1982 to investigate mechanisms underlying PCP induced psychosis. This cycle of the project will utilize information gained during previous cycles to determine the effectiveness of glycine site agonists and uptake antagonists in reversing specific behavioral and physiological effects of PCP in rodents and primates. Characteristics of specific glycine site agonists (e.g., glycine, D-serine) and glycine uptake antagonists (e.g., glycyldodecylamide) will be evaluated in rat brain homogenate. Effects of these drugs will then be evaluated relative to PCP-induced hyperactivity in rodents and PCP-induced social withdrawal and psychophysiological dysfunction in monkeys. The overall goals of the project are (1) to evaluate the likely specific usefulness of glycine site agonists/glycine uptake antagonists in the treatment of PCP psychosis and PCP psychosis-like symptoms of schizophrenia, and (2) to develop animal models sensitive to the non-dopaminergic, as well as dopaminergic, consequences of PCP-induced NMDA receptor blockade.
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