The proposed research concerns the interactions of dopamine (DA) with other classical neurotransmitters in the striatum. Interaction with DA receptors is the 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 hyperkinetic movements and psychotic symptoms. Neuroleptics, drugs which block DA receptors, are effective at treating schizophrenia, but they may cause a parkinsonian syndrome or a chronic, sometimes disabling movement disorder called tardive dyskinesia. Many of these drugs have been shown to interact with other receptors in the striatum, including those for acetylcholine, serotonin, and norepinephrine. The low incidence of motor side effects seen with the so-called atypical neuroleptics has been correlated with their anticholinergic effects. However, studies in this laboratory have demonstrated that the co-administration of an anticholinergic drug with a classic neuroleptic does not produce the same change in striatal DA receptors that administration of an atypical neuroleptic produces. It may be that understanding of the interaction of these several systems - DA, acetylcholine, serotonin, noradrenaline - is required in order to develop more effective, safer therapeutic agents. Binding studies in rat striatal membranes will establish the affinities for D-1, D-2, cholinergic, serotonergic, and Alpha-adrenergic receptors of a series of drugs in a standard fashion, using the most discriminating radioligands available. These drugs will include drugs whose clinical use is associated with troubling side effects, those whose use is not, and drugs which are of theoretical pharmacological importance. Studies of receptor regulation by chronic drug administration will be conducted in both normal rats and those with 6-OHDA lesions of the substantia nigra. Binding studies in homogenates and autoradiography of tissue sections will be used to examine changes in receptor density and distribution, respectively. 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 post-mortem human brain tissue.
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