This proposal studies a widely-used animal model of depression. Rats are exposed to shocks they cannot control, which produces behavioral changes that resemble human depression with respect to etiology, symptomatology, and responsiveness to antidepressant treatment. This model has been so successful and provocative that several laboratories have begun to utilize it vigorously. The result of this, however, is that diverse procedures are now in use which may or may not have different effects, and, consequently, the ability of researchers interested in depression to generalize findings has become a question. The first purpose is to test procedures presently used to produce this model in three major laboratories in order to determine precisely what features of depression, or characteristics, each of these different procedures will produce. These experiments should (a) form a basis for standardizing procedures used for this model based on comparative data and (b) since the model utilizes stressful conditions, provide findings that will allow investigators to minimize stressful conditions necessary to produce the model. The second purpose of the proposal is to continue studies aimed at discovering the neurochemical changes that bring about depression. Since the model under study here reproduces the characteristics of the human disorder of depression in an animal, it can be used as a tool to study changes that underlie depression. (The discrete neurochemical analysis proposed here is presently possible only in an animal model of this type.) This model has already provided some clues as to the potential underlying neuropathology in depression. Two specific mechanisms have emerged from studies of stress-induced depression, one which points to decreased release of norepinephrine (NE) in the locus coeruleus (LC) region and another which points to changes in serotonin (5-HT) release in the forebrain. We will not only examine symptomatology (i.e. behavioral indices) of depression but also, in the same animals, examine release of monoamines in vivo (by measuring concentration of the metabolites normetanephrine, DHPG, DOPAC, HVA, and 5-HIAA) to determine whether changes in release are associated with behavioral depression. Other similar experiments will directly measure release of monoamines from brain tissue in vitro (K+-stimulated release). This will test the two specific hypotheses offered to date. Further experiments will test the possibility that the two hypotheses described above are actually part of the same mechanism by manipulating the LC and dorsal noradrenergic bundle to determine if this affects 5-HT release in the forebrain and behavioral depression. Other studies will measure indices of depression after infusing noradrenergic and serotonergic agonists and antagonists into various forebrain regions in order to determine what forebrain regions are particularly important in depression in this model. Finally, the specificity of the model used in our laboratory for responsiveness to antidepressant drugs will be determined as well as how the effects of all procedures respond to anxiolytics since anxiety seems to be an important aspect of depression in this model.
