Norepinephrine and the neuropeptide, corticotropin-releasing factor (CRF) are two neurotransmitters that are altered in the brains of suicide victims. Enhanced CRF neurotransmission also mediates the responses of the rat noradrenergic locus coeruleus to stressful stimuli. Recent studies found that the human locus coeruleus receives a dense CRF innervation, thus providing anatomical evidence for a neuromodulatory role for this peptide on human noradrenergic locus coeruleus neurons. This proposal is designed to test the hypothesis that the human noradrenergic locus coeruleus system is altered in the brains of suicide victims which develops in response to a hyperactive CRF input. The specific aims of the proposed research are; I) to determine the biochemical responses of the rat locus coeruleus to acute and chronic stressors and the role of CRF in these responses; 2) determine whether the CRF afferents innervating the human locus coeruleus are altered in suicide victims and 3) determine whether the noradrenergic alteration in locus coeruleus neurons in suicide victims is at the level of gene or protein expression for the rate-limiting enzyme, tyrosine hydroxylase (TH). In situ hybridization histochemistry and Northern blot assays will be used to quantitate mRNA levels of TH and CRF in rat and human brainstem tissue sections or tissue homogenates. Western blot assays will be used to quantitate TH protein levels in locus coeruleus tissue homogenates of rat and human. The goals of the proposed experiments are to understand the adaptive neurochemical responses of the rat noradrenergic and CRF systems to stress and to utilize this information for identifying a noradrenergic defect in locus coeruleus neurons of suicide victims and the neural substrate responsible for this abnormality. Considering the role of norepinephrine and CRF in stress, affective illness and suicidality, the information generated by these studies may enhance our understanding and treatment of suicidal behavior.