Chronic systemic administration of serotonergic ligands flibanserin and 8-OH-DPAT enhance HPA axis responses to restraint in female marmosets Yves Aubert a,b, * , Michael A. Bohl a , Jason R. Lange a , Nicole R. Diol a , Kelly A. Allers c , Bernd Sommer c , Nicole A. Datson b , David H. Abbott a,d,e a Wisconsin National Primate Research Center, University of Wisconsin-Madison, WI, USA b Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Universiteit Leiden, The Netherlands c Department of CNS Diseases, Boehringer Ingelheim, Biberach, Germany d Department of Obstetrics and Gynecology, University of Wisconsin-Madison, WI, USA e Endocrinology-Reproductive Physiology Training Program, University of Wisconsin-Madison, WI, USA Received 5 December 2011; received in revised form 20 April 2012; accepted 21 May 2012 Psychoneuroendocrinology (2013) 38, 145—154 KEYWORDS Flibanserin; 8-OH-DPAT; Serotonin receptor; HPA axis; Nonhuman primate; ACTH; Cortisol; Female sexual function; HSDD; Pair behavior Summary 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-DPATadministration 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 (15 mg/kg) and an additional 8 female marmosets receiving 8-OH-DPAT (0.1 mg/kg) for 15—16 weeks. 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. * Corresponding author at: Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands. Tel.: +31 71 527 6301; fax: +31 71 527 4715. E-mail addresses: auberty@lacdr.leidenuniv.nl, yvesaubert@gmail.com (Y. Aubert). Available online at www.sciencedirect.com j our na l h omepa g e: www.e lse vie r.c om/l oca te/ psyne ue n 0306-4530/$ — see front matter # 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psyneuen.2012.05.011