ANTIPSYCHOTIC AGENTS ANTAGONIZE NONCOMPETITIVE N-METHYL-D-ASPARTATE ANTAGONIST-INDUCED BEHAVIORS

Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitive N-methyl-D-aspartate (NMDA) a ntagonist-induced behaviors. All of the agents dose-dependently antago nized the apomorphine-induced climbing mouse assay (CMA) and dizocilpi ne (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CM A/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a resul t had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, ha loperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant moto r impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0 .25 and 0.5 mg/kg) significantly reversed this social withdrawal in ra ts. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by cloz apine and olanzapine. Furthermore, assessment of the effects of antips ychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents fo r negative symptoms and treatment resistant schizophrenia.