Learned helplessness has been proposed to be an animal model of depresion. Much research has dealt with the physiological and biochemical changes associated with this syndrome. Recently, behavioral pharmacology experiments have suggested that anxiety and its biological correlates may play a role in the development of learned helplessness. To date, little work has examined central """"""""anxiety sites"""""""" and their relationship with this syndrome or with individual differences in stress reactivity. We propose to carry out in vitro radioligand (homogenate) binding and autoradiography, in vivo behavioral pharmacology and in vivo receptor binding analysis in rats to ascertain the involvement of the central benzodiazepine/GABA receptor complex and its relationship to depression in rats. These experiments will not only test the hypothesis that the benzodiazepine/GABA receptor is differentially modulated by active coping behavior (stress control) and depression, but more importantly, will examine if this site is an important link in hypothesized continuum between anxiety and the development of full-blown depression. We will employ a recently developed prescreening procedure to provide 2 behaviorally """"""""homogeneous"""""""" populations of stress-sensitive (helpless) and stress-resilient (coping) rats. Once these two populations have been identified, their pharmacological and neuro-chemical responsivity to an inescapable stressor will be characterized. Initial stress-induced changes in these sites may predict future individual differences in stress responsivity. The proposed experiments will provide preclinical evidence concerning both in vitro and functional changes of a site thought to be involved in the physiology of anxiety and how these changes correlate with active coping behavior and depression. This site will be tested for its sensitivity in predicting future stress vulnerability or resistance. The heuristic value of using animal models of psychopathology is to allow for the development of new diagnostic criteria for initiating earlier, more effective treatment for such disorders as depression. This work will aid in the development of both behavioral therapy and pharmacotherapy for stress-related disorders in humans.
