Antidepressant actions on brain noradrenergic neurons.
Corticotropin-releasing factor (CRF), the hormone 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 these 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 and 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 stimulation was somewhat enhanced in chronic SER rats. This is an effect that is opposite that produced by CRF.(ABSTRACT TRUNCATED AT 250 WORDS)
Valentino
R J
RJ
Department of Pharmacology, George Washington University Medical Center, Washington, D.C.
Curtis
A L
AL
Parris
D G
DG
Wehby
R G
RG
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism* / Q000502:physiology; D003891:Desipramine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D009431:Neural Conduction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012584:Sciatic Nerve / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology*; D020280:Sertraline
D009281:Naphthalenes; D012702:Serotonin Antagonists; D003346:Corticotropin-Releasing Hormone; D015057:1-Naphthylamine; D020280:Sertraline; D003891:Desipramine