The long-term objective of this project is to characterize the properties of different dopamine (DA)-and 5-hydroxytryptamine (5 HT)-containing neuronal systems in the rat brain. The hypothesis that will be tested is that anatomically distinct DA and 5HT neuronal systems in the brain subserve different functions and, in turn, are regulated by different mechanisms. Once the properties of the different DA and 5HT neuronal systems are characterized, and differences in the manner by which they are regulated are identified, it may be possible to utilize this information to develop drugs that will influence the activity of one neuronal system without altering the others. Such drugs may be therapeutically useful in treating mental and endocrine disorders. The characteristics of DA neurons in the major ascending mesotelencephalic systems will be compared with the little studied DA neurons which comprise the incertohypothalamic and tuberohypophysial systems. In addition, the characteristics of the major 5HT neuronal systems which originate in raphe nuclei will be compared with the recently described intrahypothalamic 5HT neurons. The activities of these various neurons will be estimated by measuring a) the concentration of metabolites (DOPAC, 5HIAA), b) rates of turnover (decline of DA after administration of a tyrosine hydroxylase inhibitor, Alpha-methyltyrosine) and synthesis (accumulation of DOPA and 5HTP following the administration of a decarboxylase inhibitor, NSD 1015) in brain and hypophysial regions that contain terminals of these neurons. The picogram concentrations of the amine neurotransmitters, their precursors, and metabolites in microdissected brain regions will be quantified using radioenzymatic assays and high performance liquid chromatography coupled to electrochemical detectors. The effects of endocrinological and pharmacological manipulations on the activities of the various 5HT and DA neuronal systems will be characterized using the techniques outlined above.
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