BRAIN AMINES--REGULATION AND FUNCTION

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The main objectives of this project are to determine the roles of catecholamines in brain functions that regulate motor activity, neuroendocrine secretion, and autonomic function in health, in disease states and in mediating responses to drugs in animals and in humans. In vivo microdialysis is used to monitor levels of monoamines and their metabolites in extracellular fluid in specific brain regions and has been combined with a parallel infusion cannula to introduce drugs or isotopically labeled compounds. Brain lesions are made surgically or by use of toxins specific to particular cell types. HPLC and liquid scintillation spectrophotometry are used in assays of materials in the microdialysates. Some studies is designed to examine the effects of a variety of stressors on brain amine release and simultaneously on levels of hormones in blood. In other studies and adrenal medullary tyrosine hydroxylase and the mRNA encoding this enzyme are assayed. In other studies, amine receptors and transporters have been examined in vitro using cells from different regions of brain and in cultured cell lines derived from the hypothalamus. Indirect evidence using blockade of serotonin (5-HT) reuptake or a neurotoxin (2,7-DHT) to destroy 5-HT neurons, suggests that 5-HT stimulates central neural DA release. Direct application of glycine also stimulates striatal DA release in conscious rats. Cerebrocortical tetrodotoxin-sensitive NE release is enhanced by chronic inhibition of monoamine oxidase A (MAO-A), but not type B. rats with unilateral striatonigral destruction with 6-OHDA, DA formation from locally perfused DOPA was less on the lesioned than on the intact side. Clorgyline (an inhibitor of MAO-A), augments DA production from DOPA both on the lesioned and the intact side, whereas deprenyl (an inhibitor of MAO-B) was without effect. Adult spontaneously hypertensive rats (SHRs) of the Okamoto strain had greater in vivo NE release and tyrosine hydroxylation in the posterolateral hypothalamus than normotensive rats of the same strain. Furthermore, juvenile SHRs had markedly greater responses of NE release and tyrosine hydroxylation in response to systemically administered yohimbine. The relationship of neuroendocrine responses to a variety of stressors (handling, immobilization, subcutaneous formalin injection, insulin, hemorrhage, or cold) evoke different patterns of responses. For example, insulin-induced hypoglycemia evoked marked, correlated increases in EPI and ACTH levels, whereas cold exposure increased plasma NE levels disproportionately compared with ACTH responses, and hypotensive hemorrhage increased ACTH levels disproportionately compared with catecholamine responses. Induction of rat adrenal tyrosine hydroxylase during immobilization stress was shown to be independent of pituitary hormones or innervation, suggesting a novel mechanism.