Schizophrenia affects nearly one percent of the human population. These individuals express a range of debilitating positive, negative and cognitive symptoms. Phencyclidine (PCP), a dissociative anesthetic and drug of abuse, induces schizophrenia-like behaviors in normal humans and in animal models. PCP exacerbates these symptoms in schizophrenic individuals. Current therapies for schizophrenia also moderate PCP-induced behaviors in animals. For these reasons, PCP administration in animals is a widely accepted model in which to study novel therapeutic approaches to schizophrenia and PCP abuse. Acute and chronic administration of d-amphetamine also induces some schizophrenia-like symtoms in humans and has been used in animal models of this disorder. N-acetylaspartylglutamate (NAAG) is a peptide transmitter that selectively activates group II metabotropic glutamate receptors (mGluRs) and is inactivated by extracellular peptidases. Agonists of group II mGluRs reduce some behavioral and neurochemical consequences of PCP in animal models. The PI's group demonstrated that inhibition of enzymes that inactivate synaptically released NAAG reduces the locomotor activity and stereotypic behaviors induced by PCP and MK-801 (open channel NMDA receptor ion channel antagonists) in rats and mice. Inhibition of NAAG peptidase activity also reduces PCP-induced negative behaviors in a resident-intruder assay in mice. NAAG activation of group II mGluRs mediates the effects of peptidase inhibition in these studies. The research proposed here will test the hypothesis that NAAG peptidase inhibitors increase extracellular NAAG levels following synaptic release with a resulting reduction in PCP- and d- amphetamine-induced schizophrenia-like behaviors in rats and mice. Neurochemical and behavioral assays will address the relationship among PCP treatment, peptidase inhibition, and transmitter release in prefrontal cortex. Possible compensation to chronic peptidase inhibition will be assessed in assays of PCP-induced positive (stereotypy), negative (resident-intruder) and cognitive (delayed alternation test of working memory) behaviors. If compensation is detected, NAAG- related neurochemical markers will be examined. The hypothesis that atypical antipsychotics and NAAG peptidase inhibition affect related but not identical behavioral pathways will be tested using NAAG peptidase inhibition as adjuvant therapy with clozapine for PCP-induced behaviors. This research is aimed at the development of an entirely novel therapeutic approach to treatment of schizohrenia and PCP as a drug of abuse. PUBLIC HEALTH RELEVANCE: Current treatments for shizophrenia are not effective in all patients. Better pharmacotherapies, particularly adjuvant therapies, are needed for treatment of this debilitating disorder. Proof of the concept that inhibition of NAAG peptidase activity reduces the behavioral effects of PCP and d-amphetamine in animal models of schizophrenia represents a major step in translating basic research on NAAG and NAAG peptidase inhibitors into human therapies for schizophrenia and acute PCP intoxication.