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

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

Yves Aubert et al. J Sex Med. 2012 Mar.

Abstract

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.

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Conflict of interest statement

DISCLOSURE/CONFLICTS OF INTEREST

Dr. Abbott reports having received a grant from Boehringer Ingelheim that supported the work of Yves Aubert, Morgan Gustison, Lindsey Gardner, Michael Bohl and Jason Lange. Dr. Allers and Dr. Sommer are employed by Boehringer Ingelheim. Dr. Datson currently holds a grant from Boehringer Ingelheim to perform molecular follow up studies of the work described here.

Figures

**Figure 1. 24-hour pharmacokinetic profiles of flibanserin and 8-OH-DPAT in female marmoset monkeys**
Pairmate observations were performed at 16–24 hours after administration, when exposure to circulating drug concentrations was low or absent, while observation of the 5-HT behavioral syndrome was performed at 0–0.5 hours after administration, when circulating drug concentrations were high. 8-OH-DPAT, R-(+)-8-hydroxy-2-(di-n-propylamino)-tetralin; 5-HT, serotonin.

**Figure 2. Investigation of female genital area**
Frequencies (backtransformed mean [+95% confidence limit]) of **(A)** female genital area self-grooming and **(B)** male inspection of female genital area per 30 minutes during 5–6 weeks following the onset of flibanserin, flibanserin vehicle, 8-OH-DPAT or 8-OH-DPAT vehicle administration. *** p=0.001 vs. flibanserin vehicle (F(1,7) = 31.3), * p=0.020 vs. flibanserin vehicle (F(1,7) = 8.9), † p=0.080 vs. 8-OH-DPAT vehicle (F(1,7) = 4.2). Each symbol indicates the same individual female marmoset receiving estradiol (solid symbols) or no estradiol (open symbols). 8-OH-DPAT, R-(+)-8-hydroxy-2-(di-n-propylamino)-tetralin.

**Figure 3. Female sexual rejection**
Frequency (backtransformed mean [+95% confidence limit]) of female rejection of male mounts and mount attempts per 30 minutes during 5–6 weeks of flibanserin, flibanserin vehicle, 8-OH-DPAT or 8-OH-DPAT vehicle administration. * p=0.024 vs. 8-OH-DPAT vehicle (F(1,7) = 8.2). Each symbol indicates the same individual female marmoset receiving estradiol (solid symbols) or no estradiol (open symbols). 8-OH-DPAT, R-(+)-8-hydroxy-2-(di-n-propylamino)-tetralin.

**Figure 4. Pairmate allogrooming and aggression**
Frequencies (backtransformed mean [+95% confidence limit]) of **(A)** allogrooming and **(B)** aggressive interactions between pairmates per 30 minutes during 5–6 weeks of flibanserin, flibanserin vehicle, 8-OH-DPAT or 8-OH-DPAT vehicle administration. *** p=0.001 vs. flibanserin vehicle (F(1,7) = 34.2), † p=0.079 vs. 8-OH-DPAT vehicle (F(1,7) = 4.2), * p=0.049 vs. 8-OH-DPAT vehicle (F(1,7) = 5.6). Each symbol indicates the same individual female marmoset receiving estradiol (solid symbols) or no estradiol (open symbols). 8-OH-DPAT, R-(+)-8-hydroxy-2-(di-n-propylamino)-tetralin.

**Figure 5. Sprawling behavior**
Latency (minutes; backtransformed mean [+95% confidence limit]) to the first occurence of sprawling behavior by female marmosets during pairmate observation after 5–6 weeks of flibanserin or flibanserin vehicle. * p=0.011 vs. flibanserin vehicle (F(1,7) = 11.90). Each symbol indicates the same individual female marmoset receiving estradiol (solid symbols) or no estradiol (open symbols).

**Figure 6. Acute induction of the 5-HT behavioral syndrome**
Frequency (backtransformed mean [+95% confidence limit]) of female **(A)** “rapid, random limb movements” behavior, **(B)** “wet dog shake” behavior, and **(C)** scratching behavior per 30 minutes during 5–6 weeks of flibanserin, flibanserin vehicle, 8-OH-DPAT or 8-OH-DPAT vehicle and following 0–0.5 hours of treatment administration. ** p<0.01 vs. 8-OH-DPAT vehicle (“rapid, random limb movements”: F(1,7) = 16.7; “wet dog shakes”: F(1,7) = 19.8), † p=0.052 vs. 8-OH-DPAT vehicle (F(1,7) = 5.46). Each symbol indicates the same individual female marmoset receiving estradiol (solid symbols) or no estradiol (open symbols). 8-OH-DPAT, R-(+)-8-hydroxy-2-(di-n-propylamino)-tetralin.

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