The International Journal of Neuropsychopharmacology

Serotonin: New Aspects of its Functions in the Brain

5-HT1A receptor antagonism reverses and prevents fluoxetine-induced sexual dysfunction in rats

Stacey J. Sukoff Rizzoa1 c1, Claudine Pulicicchioa1, Jessica E. Malberga1, Terrance H. Andreea1, Gary P. Stacka2, Zoë A. Hughesa1, Lee E. Schechtera1 and Sharon Rosenzweig-Lipsona1

a1 Wyeth Research, Discovery Neuroscience, Princeton, NJ, USA

a2 Wyeth Research, Chemical and Screening Sciences, Princeton, NJ, USA

Abstract

Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT1A antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT1A 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-HT1A 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-HT1A 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-HT1A 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-HT1A 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-HT1A antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.

(Received January 09 2009)

(Reviewed March 12 2009)

(Revised April 07 2009)

(Accepted April 09 2009)

(Online publication May 13 2009)

Correspondence:

c1 Address for correspondence: S. J. Sukoff Rizzo, Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543, USA. Tel.: 732-274-4672 Fax: 732-274-4020 Email: rizzos@wyeth.com

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