Most investigators hypothesize that immunological abnormalities that have been identified in depressed individuals are secondary to alterations in brain function, particularly in regions and systems that are implicated in the regulation of immune function. Nonetheless, this hypothesis has not been broadly tested despite evidence that immune function is normalized by antidepressant treatment in clinical populations. The proposed research will use the Flinders Sensitive Line (FSL) genetic rat model of depression to test the hypothesis that alterations in brain monoaminergic systems contribute to depression-related abnormalities of immune function. This project builds on exciting recent data showing markedly reduced in vivo type 1 immune responses in FSL rats. Two specific aims comprise the proposed research. The first stems from previous work showing that chronic antidepressant treatment with tricyclic or serotonin-specific antidepressants normalizes behavioral and neurochemical abnormalities in the FSL rats. In the proposed studies, FSL and control rats will receive chronic treatment with the antidepressants desipramine and sertraline. These treatments are expected to normalize behavioral and immunological abnormalities in the FSL animals. The second aim will test the hypothesis that chronic intracerebroventricular infusion of norepinephrine or serotonin, the pharmacological targets of desipramine and sertraline, respectively, will normalize behavioral and immunological differences between the FSL and FRL strains. These experiments will simultaneously evaluate (a) the site of action for antidepressant effects on behavior and hypothesized effects on immune function (i.e. central or peripheral), (b) the extent to which a specific monoaminergic system may play a greater role in regulating type 1 immune responses, and (c) the immunomodulatory effects of chronic elevations in brain monoamines. Collectively, these studies build on exciting new data, and they are designed as initial steps in the process of describing a seamless chain of influence originating in the brain and culminating in altered function of specific immunological cells. Because the FSL rat has already been established as a valid model for depression, the data generated from these studies promise to illuminate the integrated biological processes that produce increased vulnerability to physical illness in the clinically depressed