Behavioral and pharmacological manipulations will be used to study, in a rigorously quantitative fashion, the behavioral effects of dopamine- receptor-blocking antipsychotic drugs. Typical antipsychotic drugs produce uncomfortable and often incapacitating motor side effects that arise after both short-term (dystonia, akathisia, Parkinsonism, and cognitive impairments) and long-term (tardive dyskinesia and other tardive symptoms) therapy. Preclinical research into these side effects will contribute to their elimination, and such work is a major aim of this proposal. Four kinds of novel behavioral procedures will be used to quantify the adverse effects of neuroleptics in rats. These are 1) forelimb operant task with concurrent measurement of response force, response duration, and microcatalepsy, which provide descriptions of dystonia, bradykinesia, and immobility, respectively; 2) the sustained attention task, which models motor and cognitive side effects, provides reaction time measures, and detects akathisia in rats; 3) the forelimb tremor task, which affords a measure of Parkinson-like effects and with Fourier methods distinguishes between typical (haloperidol) and atypical (clozapine) neuroleptics; and 4) the measurement of force and rhythm of rats' tongue movements, which may provide information relevant to both neuroleptic-induced Parkinsonism and tardive dyskinesia. These rodent models will be used to pursue three interrelated themes: 1) functional differences between D1 and D2 receptor blockers as expressed in behavioral measures in intact rats; 2) quantitative behavioral differences between typical (e.g., haloperidol) and atypical neuroleptics (clozapine, risperidone, olanzapine); and 3) assessment of the interaction between dopamine receptor blockers and a variety of cholinergic, serotonergic, and glutamatergic compounds as the latter may lessen or worsen neuroleptic- induced behavioral disruptions in rats.
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