The present grant is a revision of a previous proposal, MH45265, whose aim was to elucidate the role of central alpha-l noradrenergic function in stress-induced behavioral dysfunction. The proposal is focussed on a proposed neurobiological pathway by which stress produces behavioral inactivity via a corticosterone-induced desensitization of behaviorally activating brain alpha-1 adrenergic receptors. The proposed studies will further elucidate this pathway by determining: 1) the subtype of brain alpha-1 receptor (1A, 1B or ID) that mediates behavioral activation and whether it is desensitized by stress and corticosterone as preliminary data indicate; 2) the brain region within which it acts to stimulate behavioral activity; 3) the role of endogenous corticosterone and individual corticosteroid receptors in its desensitization by stress; and 4) the role of changes in the density and coupling of this alpha-1 receptor in the mechanism of the desensitization. The proposed studies will yield important clues on the pathophysiology of inactive behavioral states occurring in several psychiatric and stress related disorders and will stimulate clinical research into possible alterations in brain alpha-l receptors that may sensitize individuals to stress-induced behavioral impairment.
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