The atypical antipsychotic drugs are a major advance over the older drugs that frequently induced extrapyramidal side effects (EPS). These newer drugs, except for clozapine, continue to induce EPS at higher doses. Despite its superior efficacy in the treatment of refractory schizophrenic patients, clozapine produces measurable cognitive side effects as well as distinctive, but not EPS-like, motor effects in both humans and rats. The over arching purpose of this proposal is to quantify, in rats and in inbred strains of mice, the motor and cognitive side effects of clozapine and other atypical antipsychotic drugs as well as to continue efforts to quantitate low-dose EPS in rodents. Three, primary behavioral measurement procedures will be used: 1) the food-anticipation-operant-microcatalepsy (FAOM) task that models low dose EPS (bouts of immobility that interrupt behavior) and bradykinesia (slowing of movements) in both rats and mice; 2) the sustained attention task (SAT) that concurrently measures reaction time and cognitive performance and closely resembles the continuous performance task that reveals deficits characteristic of schizophrenia; 3) the forelimb tremor task (FT) that uses force-transducer technology and Fourier analysis to quantify drug-induced tremor and detects the hypotonia and antitremor effects of clozapine. In the FAOM procedure, the EPS liability of atypical antipsychotics clozapine, risperidone, sertindole, quetiapine, and olanzapine will be evaluated in haloperidol-sensitized rats. When haloperidol-treated inbred strains of mice were compared in the FAOM task, the C57bl/6 mice showed striking EPS-like effects while the Balb/c mice did not-a result suggesting genetic causes. Several inbred strains of mice will be compared to identify strains likely to express EPS-like effects of atypical antipsychotic drugs. The SAT procedure will be used with rats to assess deleterious cognitive effects of chronic clozapine. The FT task will be used with rats to explore clozapine's recently discovered withdrawal effect (tremor rebound), to evaluate other atypical antipsychotics for clozapine-like motor effects, and to assess clozapine's ability to dampen tremor induced by harmaline or physostigmine.
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