Specific serotonin reuptake inhibitors (SSRIs) are the most widely prescribed drugs for treatment of depressive disorders. Preliminary data have shown that acute fluoxetine (FLX) administration significantly suppresses mitogen-induced lymphocyte proliferation and NK cell cytolytic activity. The mechanism and implications of SSRI immune suppression are not yet known. The suppressive effects were found to be dose-dependent, reversible, and selective for serotonin reuptake. The lymphocyte effects, but not NK cell affects, appear to be 5HT2A receptor mediated. These data suggest that SSRI therapy may potentiate the immunosuppression observed in depression, therefore, it is important to characterize the mechanism and effects of acute and chronic treatment with FLX. To test the hypothesis that acute and chronic SSRI treatment suppresses Cell-mediated immunity via serotonin receptor activation in normal animals and in animal models of depression, I propose to determine: 1) the serotonin receptor subtype(s) involved in the acute immunomodulatory effects of FLX, 2) the mechanism/site of action by which acute FLX suppresses immune function, 3)the effects of chronic FLX treatment on immune function in normal animals, and 4) the effects of acute and chronic FLX in an animal model for depression. The results of these studies will provide insight into the mechanism of SSRI immunomodulation and the implications they might have on depressed patients receiving SSRI therapy. In addition, these studies will increase understanding of the role of endogenous serotonergic systems in modulating the immune response.
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