Tardive dyskinesia (TD) is an iatrogenic movement disorder which compromises the treatment of 15% of the world's schizophrenic population. No treatment other than neuroleptic abstention has been proven effective for this extrapyramidal side effect. Clinical research in TD is difficult and has therefore led to the wide spread use of animal models in an attempt to characterize chronic neuroleptic effects. The best characterized animal model of TD is behavioral hypersensitivity (BH) which monitors the increased stereotypic responsiveness to dopamine (DA) agonists induced by chronic neuroleptic exposure. This proposal will focus on those pharmacotherapies which have been shown to prevent the development of BH: atypical neuroleptic administration (clozapine, thioridazine, sulpiride and molindone); concurrent lithium administration; concurrent levodopa administration; concurrent antimuscarinic administration. These treatment regimens will be compared to the chronic effects of haloperidol, chlorpromazine and fluphenazine. Since BH can be prevented by a number of therapeutic regimens which appear to involve different mechanisms, a multi-technique approach will be employed to characterize the underlying CNS profiles associated with these treatments. DA and acetylcholine metabolism (chromatography), DA and muscarinic binding studies and 2 deoxyglucose imaging studies will be performed in the laboratory rat. This data will then be compared to the alterations in apomorphine responsiveness induced by a given treatment regimen. The results will then be used to characterize the striatal and extrastriatal profiles associated with the prevention of BH in an effort to generate an animal model which can determine the extrapyramidal liabilities associated with neuroleptic therapies. Since the drug regimens studied utilize agents which already exist, the implications of this work should be immediately applicable to the clinical setting to prevent or reduce the induction of TD.
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