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Q CHANG, W LACSINA, C N. COHRON, T HANANIA

Studies have shown that animals models involved in glutamatergic pathways are important tools to study negative and cognitive symptoms of schizophrenia. NMDA receptor antagonist dizocilpine (MK-801) elicit schizophrenia-like symptoms in humans and in animal models. In the present studies, we assessed the effects of acute administrations of MK-801 on recognition memory and executive function. We also tested the efficacies of memory enhancer galantamine, antipsychotics olanzapine and clozapine, as well as selective 5-HT2A receptor antagonist volinanserin (MDL100907) in reversing the MK-801 induced deficits. Subjects were exposed to acute MK-801 (0.15 mg/kg) 30 min. prior to behavioral tests. For serial reversal learning (RVL) test, subjects had been sufficiently trained and acquired the tasks prior to MK-801 exposure. For novel object recognition (NOR) test, rats were naïve to testing prior to MK-801. In both assays, MK-801 provided deficit models in order to assess efficacies of compounds. The results indicated that MK-801 treatments induced impairments in recognition memory in NOR test and deficits in executive function in RVL test. Administration of acetylcholinesterase (AChE) inhibitor galantamine (1 mg/kg) significantly saved impairment of recognition memory in NOR test. In RVL test, olanzapine (0.3 and 1 mg/kg), clozapine (3 mg/kg) and MDL 100907 (1 mg/kg) all showed efficacy in saving reversal learning deficit caused by MK-801 treatment. These studies provide examples of memory impairment and treatment in animal models of schizophrenia, and demonstrated that deficit of executive function shown in animal models of schizophrenia are sensitive to the atypical antipsychotic clozapine and olanzapine. These results, together with our results obtained (and reported) earlier from rat models of schizophrenia using phencyclidine (PCP), are likely relevant to the cognitive impairments and negative symptoms (such as impaired social functioning shown in PCP models) of schizophrenia. Therefore these animal models can provide useful tools for the evaluation of novel antipsychotics.