The proposed studies will test the hypothesis that activity of noradrenergic neurons of the locus coeruleus (LC) is altered in depression such that spontaneous discharge rate is increased while discharge evoked by sensory stimuli is disrupted, and that part of the mechanism of action of antidepressants is to reverse these neuronal alterations. Several findings form the basis of this hypothesis. Dysfunction of central noradrenergic transmission has been implicated in depression and the LC which innervates nearly all areas of the CNS through its divergent efferent projections is the major noradrenergic nucleus in the brain. Activity of LC cells is altered by corticotropin-releasing factor (CRF) which is localized in fibers in the LC and is thought to be hypersecreted in depressed patients. CRF increases LC tonic activity and attenuates the pattern of LC discharge to phasic sensory stimuli. The hypothesis being tested predicts that antidepressants will affect LC activity in a manner opposite to CRF. Thus, antidepressants will decrease LC tonic discharge rate, enhance sensory-evoked discharge, and reverse effects of CRF.
The specific aims designed to test this neuronal hypothesis are: 1) To characterize the acute effects of antidepressants on LC spontaneous and sensory-evoked discharge of anesthetized and unanesthetized rats; 2) To determine whether acute antidepressant administration attenuates the effects of CRF on LC spontaneous or sensory-evoked discharge in anesthetized and unanesthetized rats: and 3) To determine whether LC spontaneous or sensory-evoked discharge is altered in unanesthetized rats chronically administered antidepressants. Finally, the ability of chronic antidepressant administration to attenuate CRF effects on LC activity will be determined in unanesthetized rats. The techniques required to achieve these aims involve extracellular unit recording of LC discharge in both anesthetized and unanesthetized rats. The proposed study is designed to elucidate the role of the LC- neuroendocrine relationship in depression and in the mechanism of action of antidepressant drugs.

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Hahnemann University
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