5-HT(1A) receptor antagonism reverses and prevents fluoxetine-induced sexual dysfunction in rats

Int J Neuropsychopharmacol. 2009 Sep;12(8):1045-53. doi: 10.1017/S1461145709000406. Epub 2009 May 13.

Abstract

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.

MeSH terms

  • Aminopyridines / pharmacology
  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Exploratory Behavior / drug effects
  • Female
  • Fluoxetine / pharmacology*
  • Male
  • Olfactory Bulb / injuries
  • Olfactory Bulb / physiology
  • Ovariectomy
  • Piperazines / pharmacology
  • Rats
  • Rats, Long-Evans
  • Rats, Sprague-Dawley
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Serotonin 5-HT1 Receptor Antagonists*
  • Sexual Dysfunction, Physiological / chemically induced*
  • Sexual Dysfunction, Physiological / prevention & control*
  • Time Factors

Substances

  • Aminopyridines
  • N-(2-methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexane carboxamide
  • Piperazines
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Uptake Inhibitors
  • Fluoxetine