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.
|Curtis, A L; Pavcovich, L A; Valentino, R J (1999) Long-term regulation of locus ceruleus sensitivity to corticotropin-releasing factor by swim stress. J Pharmacol Exp Ther 289:1211-9|
|Lechner, S M; Valentino, R J (1999) Glucocorticoid receptor-immunoreactivity in corticotrophin-releasing factor afferents to the locus coeruleus. Brain Res 816:17-28|
|Pavcovich, L A; Valentino, R J (1997) Regulation of a putative neurotransmitter effect of corticotropin-releasing factor: effects of adrenalectomy. J Neurosci 17:401-8|
|Lechner, S M; Curtis, A L; Brons, R et al. (1997) Locus coeruleus activation by colon distention: role of corticotropin-releasing factor and excitatory amino acids. Brain Res 756:114-24|
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|Pavcovich, L A; Valentino, R J (1995) Central regulation of micturition in the rat the corticotropin-releasing hormone from Barrington's nucleus. Neurosci Lett 196:185-8|
|Curtis, A L; Grigoriadis, D E; Page, M E et al. (1994) Pharmacological comparison of two corticotropin-releasing factor antagonists: in vivo and in vitro studies. J Pharmacol Exp Ther 268:359-65|
|Curtis, A L; Drolet, G; Valentino, R J (1993) Hemodynamic stress activates locus coeruleus neurons of unanesthetized rats. Brain Res Bull 31:737-44|
|Curtis, A L; Conti, E; Valentino, R J (1993) Cocaine effects on brain noradrenergic neurons of anesthetized and unanesthetized rats. Neuropharmacology 32:419-28|
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