This proposal is designed to evaluate the behavioral effects of antagonists of N-methyl-D-aspartate, and compare these effects to those of PCP and related compounds. Among the PCP-specific assays that will be used are PCP discrimination and catalepsy in the pigeon and ketamine discrimination in the monkey. Identification of behiaviors in the rat related to binding at the newly discovered signma receptor is the second goal of this proposal. These data may produce new leads for treatment of psychosis. Finally, procedures that may assist in measuring memory disturbances related to pharmacologically-induced Alzheimer's disease are proposed. The effects of excitatory amino acids and their antagonists will be evaluated in this procedure. These studies are predicated on recent reports of an inhibitory effect of PCP and ketamine on excitatory amino acid neurotransmission , and the finding of a novel binding site for psychotomimetic opiates. These findings have produced tremendous excitement about new drug development and the possibility of further understanding about the mechanism of action of PCP and related compounds. Because PCP is subject to abuse, produces signs similar to those of schizophrenia, is a prototype for a novel anesthetic, and has anticonvulsant activity, it is of considerable interest to evaluate its mechanism closely. Data that indicate that excitatory amino acids have neurotoxic effects, including the possibility of a relationship to Alzheimer's disease, increase interest in antagonists of excitatory amino acid actions. Most of the excitement about PCP has been generated by biochemical and electrophysiological work. It is essential that careful behavior studies be undertaken using the new drugs that have been recently synthesized or identified as being related to excitatory amino acid transmission. Behavioral data will permit a more rational integration of information coming from other in vivo and in vitro procedures.
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