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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Allegheny University of Health Sciences
Schools of Medicine
United States
Zip Code
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
Valentino, R J; Chen, S; Zhu, Y et al. (1996) Evidence for divergent projections to the brain noradrenergic system and the spinal parasympathetic system from Barrington's nucleus. Brain Res 732:1-15
Curtis, A L; Pavcovich, L A; Grigoriadis, D E et al. (1995) Previous stress alters corticotropin-releasing factor neurotransmission in the locus coeruleus. Neuroscience 65:541-50
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
Valentino, R J; Foote, S L; Page, M E (1993) The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses. Ann N Y Acad Sci 697:173-88
Curtis, A L; Drolet, G; Valentino, R J (1993) Hemodynamic stress activates locus coeruleus neurons of unanesthetized rats. Brain Res Bull 31:737-44

Showing the most recent 10 out of 21 publications