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

• Published in: Psychoneuroendocrinology Vol. 38; no. 1; pp. 145 - 154
• Main Authors: Aubert, Yves, Bohl, Michael A, Lange, Jason R, Diol, Nicole R, Allers, Kelly A, Sommer, Bernd, Datson, Nicole A, Abbott, David H
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2013
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin; 8-Hydroxy-2-(di-n-propylamino)tetralin - toxicity; 8-OH-DPAT; ACTH; Adrenocorticotropic hormone; Adrenocorticotropic Hormone - secretion; Aggression; Aggression - drug effects; Aggression - physiology; Animals; Benzimidazoles - toxicity; Callithrix; Cortisol; Endocrinology & Metabolism; Estradiol - administration & dosage; Female; Female sexual function; Flibanserin; HPA axis; HSDD; Hydrocortisone; Hydrocortisone - secretion; Hypothalamic-pituitary-adrenal axis; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - physiology; Libido - drug effects; Libido - physiology; Male; Nonhuman primate; Ovariectomy; Pair behavior; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - physiology; Psychiatry; Receptor, Serotonin, 5-HT1A - physiology; Receptor, Serotonin, 5-HT2A - physiology; Restraint, Physical - physiology; Serotonin 5-HT1 Receptor Agonists - toxicity; Serotonin 5-HT2 Receptor Antagonists - toxicity; Serotonin Agents - pharmacology; Serotonin receptor; Serotonin S1 receptors; Serotonin S2 receptors; Sexual behavior; Sexual Behavior, Animal - drug effects; Sexual Behavior, Animal - physiology; Sexual receptivity; Social behavior; Stress; Female sexual function; Flibanserin; Serotonin receptor; Nonhuman primate; Pair behavior; ACTH; HPA axis; Cortisol; HSDD; 8-OH-DPAT
• ISSN: 0306-4530; 1873-3360
• DOI: 10.1016/j.psyneuen.2012.05.011

Summary Background Flibanserin, a novel serotonin (5-HT)1A agonist and 5-HT2A 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-HT1A agonist 8-OH-DPAT suppresses female sexual behavior and increases aggressive interactions between pairmates. Activation of 5-HT1A and 5-HT2A 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-HT1A 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-HT1A 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-HT1A agonist challenge after chronic flibanserin and 8-OH-DPAT treatments indicate little or no de-sensitization of the HPA axis to repeated 5-HT1A 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-HT1A activation and concurrent 5-HT2A 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.