Results from this laboratory suggest that the stress-related neurohormone, corticotropin-releasing factor (CRF) serves as a neurotransmitter in the noradrenergic nucleus locus coeruleus (LC). Clinical studies suggest that CRF is hypersecreted in depression. Because depression is characterized by both neuroendocrine and biogenic amine dysfunctions, the effects of CRF hypersecretion on biogenic amine dysfunctions, the effects of CRF hypersecretion on biogenic amine nuclei (i.e., the LC) may be a link between these dysfunctions in depression and may be a common target of action for the mechanism of antidepressants. The hypotheses of this proposal are that CRF hypersecretion in depression results in altered LC discharge characteristics and that antidepressant treatments prevent this by interfering with CRF neurotransmission in the LC. This could occur by: 1) Pharmacologic antagonism of CRF; 2) Functional antagonism of CRF; or 3) Attenuation of CRF release. Supporting this, progress made during the previous funding period demonstrated that 4 pharmacologically distinct antidepressants share the potential to interfere with CRF neurotransmission in the LC after chronic administration. Sertraline and phenelzine altered LC sensory-evoked discharge in a manner opposite to CRF, suggesting that they could functionally antagonize CRF. Desmethylimipramine and mianserin attenuated stress-elicited CRF-dependent LC activation, suggesting that they attenuate CRF release. The proposed Aims will further test the hypotheses: 1) Determine whether other antidepressant treatments interfere with CRF neurotransmission in the LC in anesthetized rats. Previous studies of acute and chronic antidepressant effects on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by CRF, and LC activation by a stressor which requires CRF release will be extended to include other antidepressants and electroconvulsive shock; 2) Extend previous studies of the acute and chronic effects of antidepressants on LC spontaneous discharge, sensory-evoked discharge, activation by CRF and activation by stress to unanesthetized rats. LC spontaneous discharge, auditory-evoked discharge, activation by CRF and activation by hemodynamic or noise stress will be recorded and compared in unanesthetized rats administered antidepressants or vehicle; 3) Characterize LC discharge and the effects of antidepressants in models of CRF hypersecretion. CRF hypersecretion will be mimicked by adrenalectomy, chronic stress, and chronic i.c.v. administration of CRF. The effects of these manipulations on LC spontaneous and sensory- evoked discharge, and the ability of antidepressants to reverse these effects will be determined; and 4) Investigate possible mechanisms by which antidepressants interfere with CRF neurotransmission in the LC by elucidating their site of action. It will be determined whether antidepressants act within the LC or on LC afferents to produce effects that interfere with CRF function in the LC. The proposed studies will help elucidate neurotransmitter pathology in depression, mechanisms of action of antidepressant treatments, and interactions between neuroendocrine and catecholamine systems.
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