This project proposes studies aimed at elucidating the pathophysiology of depressive illness, one of the most common disturbances of mental and psychological function. Recent investigations including those from our laboratory, have implicated the brain alpha2 adrenoceptor as being responsible for at least some aspects of depressive disorders. Antidepressant drugs have significant interactions with alpha2 adrenoceptors which may be related to the antidepressant action of these agents. An alpha2 adrenergic hypothesis of depression has thus been formulated. Is order to test this hypothesis, an accurate and accessible model of the brain alpha2 adrenoceptor is needed. The platelet alpha2 adrenoceptor may be such an ideal model. The overall goals of the proposed research are (a) to establish the platelet alpha2. receptor as a peripheral model of the brain alpha2 receptor and (b) to determine whether alpha2 receptors is postmortem brains of depressed suicide victims are altered in a manner similar to that found in platelet alpha2 receptors in depressed patients. Platelets from depressed patients display significantly elevated binding of the noradrenergic agonist 3H-p-aminoclonidine (3H-PAC). The specific aims of the research proposal seek to achieve the above stated goals. First, it will be determined whether the platelet alpha2 receptor is indeed an accurate model of the brain alpha2 receptor by further characterizing the binding of 3H-PAC using platelets from healthy control subjects and cerebral cortex from non-psychiatric accidental death victims. We will utilize binding assays and the powerful and elegant technique of quantitative receptor autoradiography. Second, it will be determined whether there is a circadian or menstruation-related variation in platelet receptor binding. Third, the kinetic parameters in postmortem brains of suicide victims will be established and compared with platelets. Fourth, the subtypes of alpha2 receptors is discrete regions of postmortem brains will be examined. It is hoped that completion of these studies will aid in the development of improved methods to diagnose and treat depressive illness.