Although emotional stress is thought to contribute to a variety of cardiovascular disorders, little is known about the CNS pathways mediating its manifestations. Knowledge about the neuropharmacology of these pathways might suggest new strategies for drug therapy aimed at better controlling the response to stress. The focus of this proposal is the dorsomedial hypothalamic nucleus (DMN) of the rat, where (1) blockade of GABAergic inhibition or stimulation of excitatory amino acid receptors triggers a pattern of physiological changes that mimic those seen in acute stress, and (2) stimulation of GABAA receptors or blockade of excitatory amino acid receptors markedly reduces or blocks the changes in heart rate and blood pressure normally seen in experimental stress. The work proposed will test and expand upon the hypothesis that inhibitory and excitatory amino acid-mediated neurotransmission in the DMN of the rat influences a population of neurons whose activation is responsible for generating the integrated multi-system CNS response to stress. We propose to (1) further examine the pharmacology of the DMN and the role of this region in the response to stress. We will study the cardiovascular and behavioral effects of microinjecting agents affecting synaptic communication mediated by excitatory and inhibitory amino acids and other selected putative neurotransmitters/neuromodulators in anesthetized and conscious rats, and assess the impact of selected treatments on the cardiovascular response to stress; (2) explore the role of the paraventricular hypothalamic nucleus and the mesencephalic periaqueductal grey as well as the participation of the neuropeptides oxytocin and corticotropin releasing factor (CRF) in generating the cardiovascular changes seen upon activation of the DMN and in stress. We will examine the effects of discrete microinjections of drugs affecting GABAA and excitatory amino acid receptors into these regions and central administration of peptide antagonists on the cardiovascular response to stress and to activation of the DMN; and (3) employ the technique of in vivo microdialysis of the DMN with dihydrokainate, an inhibitor of glutamate uptake, to elevate extracellular levels of the endogenous excitatory amino acids glutamate and aspartate, and examine the effects of cardiovascular function under basal conditions in anesthetized or unstressed rats, and in stressed animals.
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