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.
Wisconsin National Primate Research Center, University of Wisconsin-Madison, WI, USA. auberty@lacdr.leidenuniv.nl
Yves
Y
Aubert
Michael A
MA
Bohl
Jason R
JR
Lange
Nicole R
NR
Diol
Kelly A
KA
Allers
Bernd
B
Sommer
Nicole A
NA
Datson
David H
DH
Abbott
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000633:toxicity*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000374:Aggression / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001562:Benzimidazoles / Q000633:toxicity*; D002144:Callithrix; D004958:Estradiol / Q000008:administration & dosage; D005260:Female; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000502:physiology; D007989:Libido / Q000187:drug effects / Q000502:physiology; D008297:Male; D010052:Ovariectomy; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000502:physiology; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology; D012149:Restraint, Physical / Q000502:physiology*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000633:toxicity*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000633:toxicity*; D018490:Serotonin Agents / Q000494:pharmacology*; D012726:Sexual Behavior, Animal / Q000187:drug effects* / Q000502:physiology
D001562:Benzimidazoles; D044402:Receptor, Serotonin, 5-HT2A; D058825:Serotonin 5-HT1 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D018490:Serotonin Agents; D044282:Receptor, Serotonin, 5-HT1A; C098107:flibanserin; D004958:Estradiol; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone