Chronic systemic administration of serotonergic ligands flibanserin and 8-OH-DPAT enhance HPA axis responses to restraint in female marmosets.

BACKGROUND: Flibanserin, a novel serotonin (5-HT)(1A) agonist and 5-HT(2A) antagonist, has been shown to increase sexual desire and reduce distress in women with Hypoactive Sexual Desire Disorder (HSDD). In marmoset monkeys, flibanserin has demonstrated pro-social effects on male-female pairmates, while the classic 5-HT(1A) agonist 8-OH-DPAT suppresses female sexual behavior and increases aggressive interactions between pairmates. Activation of 5-HT(1A) and 5-HT(2A) receptors is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. This study aims to characterize the effects of repeated flibanserin and 8-OH-DPAT administration on the marmoset HPA axis and to elucidate endocrine correlates of altered marmoset pair behavior. METHODS: Adrenocorticotropic hormone (ACTH) and cortisol were examined at baseline and during 5-HT(1A) agonist and restraint challenges in 8 female marmoset monkeys receiving daily flibanserin (15mg/kg) and an additional 8 female marmosets receiving 8-OH-DPAT (0.1mg/kg) for 15-16weeks. Corresponding vehicle treatments were administered in a counterbalanced, within-subject design. All females were housed in stable male-female pairs. Treatment-induced changes in ACTH and cortisol levels were correlated with previously assessed marmoset pair behavior. RESULTS: While morning basal cortisol levels and HPA responses to a 5-HT(1A) agonist challenge were not altered by chronic flibanserin or 8-OH-DPAT, both treatments increased the responsiveness of the marmoset HPA axis to restraint. Enhanced ACTH responses to restraint correlated with reduced sexual receptivity and increased aggression in 8-OH-DPAT-, but not in flibanserin-treated female marmosets. CONCLUSIONS: Unaltered HPA responses to a 5-HT(1A) agonist challenge after chronic flibanserin and 8-OH-DPAT treatments indicate little or no de-sensitization of the HPA axis to repeated 5-HT(1A) manipulation. Chronic 8-OH-DPAT, but not flibanserin, leads to aggravated ACTH responses to stress that may contribute to anti-sexual and anti-social behavior between 8-OH-DPAT-treated females and their male pairmates. Despite similar flibanserin and 8-OH-DPAT induced ACTH responses to restraint stress, flibanserin-treated females show unchanged cortisol profiles. This is possibly due to flibanserin's regional selectivity in 5-HT(1A) activation and concurrent 5-HT(2A) inhibition. The contrasting restraint-related cortisol responses emulate contrasting behavioral phenotypes of diminished pair-bond of 8-OH-DPAT-treated females compared to the more affiliative pair-bond of flibanserin-treated females.

Flibanserin and 8-OH-DPAT implicate serotonin in association between female marmoset monkey sexual behavior and changes in pair-bond quality.

INTRODUCTION: Psychopathological origins of personally distressing, hypoactive sexual desire disorder (HSDD) in women are unknown, but are generally attributed to an inhibitory neural regulator, serotonin (5-HT). Flibanserin, a 5-HT(1A) agonist and 5-HT(2A) antagonist, shows promise as a treatment for HSDD. AIM: To test the hypothesis that female marmoset sexual behavior is enhanced by flibanserin and diminished by 8-OH-DPAT, in order to evaluate the efficacy of serotonergic modulation of female sexual behavior in a pairmate social setting comparable to humans. METHODS: Sexual and social behavior were examined in eight female marmoset monkeys receiving daily flibanserin (15 mg/kg), 8-OH-DPAT (0.1 mg/kg), or corresponding vehicle for 15-16 weeks in a counterbalanced, within-subject design, while housed in long-term, stable male-female pairs. MAIN OUTCOME MEASURES: Marmoset pairmate interactions, including sexual and social behavior, were scored during weeks 5-6 of daily flibanserin, 8-OH-DPAT or vehicle treatment. 24-hour pharmacokinetic profiles of the drugs and their metabolites, as well as drug-induced acute symptoms of the 5-HT behavioral syndrome were also assessed. RESULTS: Two-way analysis of variance reveals that flibanserin-treated females attract more male sexual interest (P=0.020) and trigger increased grooming (P=0.001) between partners. In contrast, 8-OH-DPAT-treated females show increased rejection of male sexual advances (P=0.024), a tendency for decreased male sexual interest (P=0.080), and increased aggression with their male pairmates (P=0.049). CONCLUSIONS: While 8-OH-DPAT-treated female marmosets display decreased sexual receptivity and increased aggressive interactions with their male pairmates, flibanserin-treated female marmosets demonstrate increased affiliative behavior with their male pairmates. Such pro-affiliation attributes may underlie flibanserin's effectiveness in treating HSDD in women.