NEUROLEPTICS, SIGMA SITES AND NEUROTOXICITY

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The purpose of this project is to determine the nature of the down- regulation of haloperidol-sensitive dextromethorphan/sigma binding sites. These studies have important implications for the understanding of neuroleptic-induced tardive side effects. Long term treatment with neuroleptics is known to produce marked side effects, some of which are irreversible. This study will focus on the effects of haloperidol, other neuroleptics and their metabolites. Chronic administration of haloperidol produces a down-regulation of dextromethorphan/sigma binding sites in mice, rats and guinea pigs. This has been confirmed in our laboratory. Besides, preliminary experiments have demonstrated that some metabolites of haloperidol produced a raid marked and long-lasting inhibition of the dextromethorphan/sigma sites. The temporal characteristics of these changes are indicative of a neurotoxic phenomenon. The nature of the inhibition observed will be studied using radioreceptor assays followed by computer-assisted modeling. This will indicate the type of site that is down-regulated. Radioreceptor autoradiography will be used to locate the most sensitive areas in the brain, and histopathologic techniques to determine signs of neurotoxicity. This is an important component of the proposed research because it has been described that there are histopathologic changes in brain nuclei of patients that developed tardive dyskinesia after prolonged neuroleptic administration. Mice, rats and guinea pigs will be used to determine whether there is any species difference. This study has important implications for the understanding of the long-term extrapyramidal motor side effects of neuroleptics, such as tardive dyskinesia.