Functionally, the basal ganglia consists of the striatum, the pallidum and the substantia nigra. These nuclei are a target for drugs used in the treatment of number of neuropsychiatric disorders, and are implicated in chronic neuronal dysfunctions such as Parkinson's disease, Huntington's chorea and tardive dyskinesia. GABA, an inhibitory neurotransmitter synthesized by glutamic acid decarboxylase (GAD) is the major neurotransmitter in these nuclei. We have shown that levels of GAD and GAD mRNA are modified in neurons of the basal ganglia after lesions of cortical and dopaminergic afferents, and chronic administration of antipsychotics. These observations suggest that GAD gene expression is regulated in GABA- ergic neurons in response to alteration of their activity and reveal novel information on the long term effects of lesions and pharmacological treatments on discrete populations of basal ganglia neurons. The research proposed in this application will extend this analysis to the role of other key neurotransmitter systems of the basal ganglia in regulating GAD gene expression in these brain regions. Three major sets of neurons will be examined: the subthalamic nucleus, the serotonergic projection from midbrain raphes, and intrastriatal cholinergic neurons. An additional goal will be to compare the regulation of genes encoding two distinct isoforms of GAD (Molecular weight 65,000 and 67,000 daltons) and of the corresponding immunoreactive proteins. For mRNAs, the main method of approach will be in situ hybridization histochemistry and quantitative autoradiography at the single-cell level in topographically identified neurons. The levels of GAD mRNA will be compared to those of each GAD isoform by quantitative immunohistochemistry with monospecific antibodies. Results will be compared with changes in the level of enkephalin and substance P mRNAs, neuropeptides co-localized with GABA in distinct subsets of striatal efferent neurons. The results of these experiments will provide new insights into the molecular regulation of GABA-ergic neurotransmission in the brain. In addition, by providing unique information on the effect of drugs used in the treatment of psychiatric illness on subpopulations of GABA-ergic neurons in the basal ganglia, the results will help to identify new directions in the treatment of psychiatric symptoms in diseases of the basal ganglia, and help in the development of antipsychotic drugs with less extrapyramidal side effects.
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