Stress can be a major factor in health and disease, yet we do not understand its mechanisms. The proposed research is designed to characterize the responses of cerebral catecholamines and indoleamines in stress, and the relationships between them and the activation of the pituitary-adrenal system. In the brain, stress activates the release of norepinephrine (NE) and serotonin (5-HT) throughout the brain, and the release of dopamine (DA) in certain regions, notably frontal cortex. Using high-performance liquid chromatography (HPLC) with electrochemical detection, all three amines and their major catabolites can be measured simultaneously. These are: for NE, normetanephrine and 3-methoxy, 4-hydroxyphenylglycol (MHPG); for DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 3-methoxytyramine (3-MT); and for 5-HT, 5-hydroxyindoleacetic acid (5-HIAA). Measurement of the catabolites provides as sensitive method for the determination of activation, without the use of drugs or tracers. It is proposed to characterize the cerebral responses to footshock, restraint a other stressors, using a variety of different parameters, and both acute and chronic treatments. Potential correlations between the responses in DOPAC, HVA, MHPG, 5-HIAA, and corticosterone will be examined. This is to determine the differential sensitivity of the various responses, and whether there are conditions under which they can be dissociated. The latter would be particularly important for the understanding of their physiological roles. Other studies will be concerned with the responses to conditioned stressors, and the existence of a putative mouse pheromone signaling stress. The potential role of hormones of the pituitary-adrenal system in mediating these responses, especially that of DA in frontal cortex, will also be investigated. The mechanisms of the activation of frontal cortex DA terminals will be investigated with particular reference to the roles of the synthetic enzyme, tyrosine hydroxylase, and presynaptic autoreceptors. A comparison of the activation of synthesis in DA and NE terminals during stress will also be made. Finally, the ability of benzodiazepines and of neurotensin to counteract or diminish the stress responses will be examined.
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