BIOPHYSICAL ANALYSIS OF NEUROLEPTICS' BEHAVIORAL EFFECTS

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The proposed experiments will use behavioral, pharmacological, and neural manipulations to investigate, in a rigorously quantitative fashion, the behavioral effects of dopamine-receptor-blocking antipsychotic drugs. The major limiting factor in using these drugs to treat schizophrenia is the development of uncomfortable and often incapacitating motor side effects that frequently arise after both short-term (Parkinsonism, acute dystonia, akathisia) and long-term (tardive dyskinesia) therapy. Successful elimination of these side effects from antipsychotic drug profiles will be greatly aided by the use of preclinical test procedures that are extremely sensitive to motor side effects. Continued development of such procedures is a major aim of this proposal. Three kinds of novel behavioral procedures will be used to measure motor, incentive/motivational, and associative effects of dopamine receptor blockade: (1) the forelimb operant task for measuring the peak force, duration, and rate of relatively rapid, ballistic responses; (2) the forelimb tremor task that permits Fourier analysis of force oscillations and concomitant electromyographic recordings from the forelimb or tongue during bouts of continuous contact with a force transducer; (3) a sustained attention task in which discriminative errors of omission and commission can be correlated with reaction time. Although each procedure emphasizes a different behavioral capacity, all tasks are designed to provide detailed quantitative measures of motor function. Both D1 and D2 dopamine receptor blockers (and clozapine) will be studied in these paradigms in subchronic dosing regimes (2-6 wk). To establish further parallels between neuroleptic-induced Parkinsonism in human patients and neuroleptics' effects in these rodent-based tasks, anticholinergic antagonism of neuroleptics' effects of unilateral brain dopamine depletion on forelimb function in a two-operandum variant of the tremor task, and effects of D1 and D2 agonists and antagonists will be evaluated in this experiment.