Non-competitive and competitive N-methyl-D-aspartate receptor (NMDAR) antagonists have the ability to induce schizophrenia-like psychosis as shown in the phencyclidine (PCP) model of schizophrenia. However, the mechanism by which NMDAR antagonists produce schizophrenia-like psychosis is not well understood. The systemic administrations of non-competitive and competitive NMDAR antagonists also induce neuronal injury in limbic forebrain including the hippocampus. Several lines of evidence suggest that this NMDAR antagonist-induced neurotoxicity may be closely associated with NMDAR antagonist-induced psychosis. Evidence from human studies indicates that hippocampal disturbances may play a central role in the pathophysiology of schizophrenia. Since NMDAR antagonists induce schizophrenia-like psychosis, and produce neurotoxicity in the hippocampus, the best documented locus of pathology in schizophrenia, this study on the mechanisms by which NMDAR antagonists induce neurotoxicity in the hippocampus may provide a significant contribution toward understanding the pathophysiology of schizophrenia. In this proposal, I will examine the neurotoxic consequences of in vivoexposure to PCP and the preventive action of s-amino butyric acid (GABA) agonists in the hippocampus to investigate the mechanism by which NMDAR antagonists induce neurotoxicity with the three specific aims; 1) assess morphological injury induced by the administration of PCP and the preventive action of GABAergic agonists, 2) assess electrophysiological impairment induced by the administration of PCP and the preventive action of GABA agonists, and 3) assess changes in glutamate and GABA release induced by the administration of PCP and the preventive action of GABAergic agonists.
