The proposed research, concerning the interactions of drugs with receptors for dopamine (DA) and other classical neurotransmitters in the striatum, will concentrate initially on the D1 and D2 subtypes of DA receptors. Interaction with the D2 receptor is the apparent basis for the pharmacologic efficacy of two major classes of drugs which have revolutionized the treatment of patients with Parkinson's disease and schizophrenia. Drugs that replace DA at the synapse are effective in treating patients with Parkinson's disease but they may cause disturbing side effects of dyskinesia and psychotic symptoms. Antipsychotic drugs, or neuroleptics, are effective at treating schizophrenia, but they may cause a parkinsonian syndrome or tardive dyskinesia. Results of recent studies suggest that there are complex interactions of D1 and D2 receptors in behaviors formerly thought to be mediated solely by D2 receptors. Regulation of the densities of D1 and D2 receptors by the administration of DA agonists and antagonists that are nonselective or are selective for one subtype, and by other neuroleptics, will be investigated in the basal ganglia and other brain regions in rats. The administration of antiparkinsonian drugs and the intrastriatal transplantation of nigral or other tissue will be studied in two rodent models of parkinsonism - 6-OHDA-treated rats and MPTP-treated mice. The administration of neuroleptics and antiparkinsonian drugs will be studied as a means to increase our understanding of the way in which these drugs exert both their therapeutic and their unwanted effects. While the study of DA receptors is central to this proposal, the interaction of neuroleptic drugs with other receptors cannot be ignored in evaluating the actions of these drugs in the brain, and in understanding their implications for naturally-occurring movement disorders. Alterations in the densities and properties of other receptors with which these drugs interact - including 5-HT2, muscarinic, and Alpha-1-adrenergic - will also be investigated. Quantitative autoradiographic studies in brain sections will be used to examine changes in the densities of receptors in the basal ganglia and other brain regions. Relevance of these receptor changes will be examined by measuring alterations in the receptor-effector systems adenylate cyclase and phosphoinositide turnover. Relevance of receptor changes to the behavioral output of the striatum will be assessed by monitoring the sensitivity of treated rats to apomorphine-induced stereotypy (related to DA) and quipazine-induced """"""""wet dog shakes"""""""" (related to serotonin). Hypotheses generated by these animal studies, regarding alterations that might be expected to occur in humans treated with these drugs or in humans with the diseases Parkinsonism and schizophrenia, will be examined by study of postmortem human brain tissue.
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