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 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 (pseudoparkinsonism, 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 animal-based procedures is a major aim of this proposal. Behavioral techniques (with rats as subjects) will include both operant and nonoperant methods that permit the assessment of drug effects on forelimb usage, tongue usage, and whole body postural responses. Foremost among the behavioral methods will be the measurement of force-time waveforms of operant responses. Included in the nonoperant procedures are measures of the fine motor characteristics of licking and quantification of postural adjustments during a beam balancing task. These latter two techniques make it possible to measure behavioral effects of neuroleptics at doses that usually abolish operant responding. Pharmacological manipulations will include dose, Dl vs D2 receptor blockers, and various classes of CNS-active drugs besides neuroleptics. Neuroleptics will be examined in both chronic and acute dosing paradigms. In the chronic dosing experiments, measurement of forelimb usage and of tongue usage will be conducted in chambers where the rats live continuously (24 hr/day) for several months. By continuously monitoring two separate response systems (forelimb and tongue) from the very beginning of dosing with haloperidol decanoate it should be possible to evaluate both early onset and late onset motor effects of continuous dosamine receptor blockade in the same subjects in one experiment. The GABA hypothesis of tardive dyskinesia will be addressed by assaying the substantia nigras for GAD activity in the rats treated chronically with haloperidol. Neural manipulations will be in the form of neurotoxic lesions of the ventrolateral and dorsomedial striatum. And the effects of these lesions on forelimb usage, tongue usage, and whole body postural adjustments will be compared with the effects of neuroleptics on these same measures.