Early maternal separation is a model of major depressive disorder, as numerous preclinical studies have demonstrated that maternally-separated (MS) animals exhibit behavioral, physiologic, and neuroendocrine aberrations characteristic of depression. For example, both untreated depressed patients and MS rats experience an apparent increase in limbic and hypothalamic expression of corticotropin-releasing factor (CRF), a neuropeptide which coordinates the mammalian stress response. Utilizing this maternal separation model, we aim to test the hypotheses that CRF is involved in the pathophysiology of depression and serves as a common mediator of antidepressant efficacy. These hypotheses will be investigated in six specific aims. The first and second experiments will evaluate basal and stress-induced regional CRF and CRF receptor expression in MS rats vs. controls. The third and fourth experiments will establish whether or not chronic treatment with three pharmacologically-distinct antidepressants reverses the maternal separation phenotype and selectively decreases regional CRF expression in MS rats, thus supporting or refuting the hypothesis that CRF is a common mediator of antidepressant efficacy. The fifth and sixth experiments will test the hypotheses that, following antidepressant withdrawal, chronically-treated maternally-separated rats relapse into the maternal separation phenotype and exhibit a temporal increase in regional CRF expression. These experiments will provide further evidence to support or refute CRF's role in the pathophysiology of depression and determine whether or not this peptide is a common mediator of antidepressant efficacy.
