Antidepressant actions on brain noradrenergic neurons
Valentino, R.J.; Curtis, A.L.; Parris, D.G.; Wehby, R.G.
Journal of Pharmacology and Experimental Therapeutics 253(2): 833-840
1990
ISSN/ISBN: 0022-3565 PMID: 2338658 Document Number: 364368
Corticotropin-releasing factor (CRF), the hromone responsible for adrenocorticotropin release during stress, is thought to be hypersecreted in depression. Because recent studies suggest that CRF may serve as a neurotransmitter in the major noradrenergic nucleus, locus coeruleus (LC), it was hypothesized that antidepressants interfere with the putative neurotransmitter role of CRF in the LC by either: 1) decreasing release of CRF: 2) pharmacologically antagonizing CRF; or 3) functionally antagonizing CRF by producing effects on LC cells that oppose those of CRF. In order to test this hypothesis, the effects of acute and chronic administration of two antidepressants, a norepinephrine re-uptake inhibitor (desmethylimipramine, DMI) and a serotonin re-uptake inhibitor (sertraline, SER), on LC spontaneous discharge, LC sensory evoked discharge, LC activation by a stressor and LC activation by CRF, were compared in halothane-anesthetized rats. Acute i.v. administration of DMI decreased both LC spontaneous discharge evoked by repeated sciatic nerve stimulation. In contrast, acute i.v. SER administration decreased only evoked LC discharge rate. Chronic DMI administration (10.0 mg/kg/day, i.p., 21 days) resulted in tolerance to its effects on spontaneous and sensory-evoked LC discharge. However, chronic DMI administration attenuated LC activation by hemodynamic stress, which is thought to require CRF release. LC activation by intracerebroventricular CRF was not altered in the chronic DMI rats. In contrast to DMI, chronic SER (10 mg/kg/day, i.p., 21 days) did not alter LC activation by either stress of CRF. However, the response of LC cells to repeated sciatic nerve stimualtion was somewhat enhanced in chronic SER rats. This is an effect that is opposite that produced by CRF. The present results are consistent with the hypothesis that antidepressants interfere with CRF effects in the LC. Thus, chronic administration of norepinephrine re-uptake inhibitors may attenuate stress-elicited LC activation, which required CRF release, whereas antidepressants that are selective serotonin re-uptake inhibitors may functionally antagonize CRF effects on LC by producing opposing effects.