5-HT(1A) receptor antagonism reverses and prevents fluoxetine-induced sexual dysfunction in rats.
Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT(1A) antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT(1A) antagonism on antidepressant-induced side-effects has not been fully examined. The present study was conducted to evaluate the ability of acute or chronic treatment with 5-HT(1A) antagonists to alter chronic fluoxetine-induced impairments in sexual function. Chronic 14-d treatment with fluoxetine resulted in a marked reduction in the number of non-contact penile erections in sexually experienced male rats, relative to vehicle-treated controls. Acute administration of the 5-HT(1A) antagonist WAY-101405 resulted in a complete reversal of chronic fluoxetine-induced deficits on non-contact penile erections at doses that did not significantly alter baselines. Chronic co-administration of the 5-HT(1A) antagonists WAY-100635 or WAY-101405 with fluoxetine prevented fluoxetine-induced deficits in non-contact penile erections in sexually experienced male rats. Moreover, withdrawal of WAY-100635 from co-treatment with chonic fluoxetine, resulted in a time-dependent reinstatement of chronic fluoxetine-induced deficits in non-contact penile erections. Additionally, chronic administration of SSA-426, a molecule with dual activity as both a SSRI and 5-HT(1A) antagonist, did not produce deficits in non-contact penile erections at doses demonstrated to have antidepressant-like activity in the olfactory bulbectomy model. Taken together, these data suggest that 5-HT(1A) antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.
Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543, USA. rizzos@wyeth.com
Stacey J
SJ
Sukoff Rizzo
Claudine
C
Pulicicchio
Jessica E
JE
Malberg
Terrance H
TH
Andree
Gary P
GP
Stack
Zoë A
ZA
Hughes
Lee E
LE
Schechter
Sharon
S
Rosenzweig-Lipson
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D009830:Olfactory Bulb / Q000293:injuries / Q000502:physiology; D010052:Ovariectomy; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D012735:Sexual Dysfunction, Physiological / Q000139:chemically induced* / Q000517:prevention & control*; D013997:Time Factors
D000631:Aminopyridines; D005473:Fluoxetine; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C514231:N-(2-methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexane carboxamide