Bremelanotide: An Overview of Preclinical CNS Effects on Female Sexual Function

Abstract

Introduction Bremelanotide is an analogue of the naturally occurring peptide α-melanocyte-stimulating hormone (α-MSH). It stimulates erection in men and male rats, and is currently in clinical trials for the treatment of erectile dysfunction. Aim To review the effects of bremelanotide, an analogue of the naturally occurring peptide α-MSH, on the preclinical indices of sexual desire in female rats, and where in the brain these actions may occur. Main Outcome Measures Appetitive sexual behaviors, such as solicitations, hops and darts, and pacing, were assessed along with consummatory behaviors such as lordosis. The involvement of brain regions was assessed following direct administration to the region, by the stimulation of molecular markers of neural activation, and using microdialysis to examine extracellular fluid for different neurotransmitters. Methods Using a model that allows ovariectomized, hormone-primed female rats to control the timing of sexual encounters with males, we tested the ability of bremelanotide to increase appetitive (proceptive) and/or consummatory sexual behaviors. Results Bremelanotide dramatically and selectively increased measures of solicitation in female rats, without altering pacing or lordosis, following both peripheral (subcutaneous) administration or infusions directly into the lateral ventricles or medial preoptic area (mPOA), but not the ventromedial hypothalamus. The mPOA is critical for the display of appetitive sexual behaviors in females and males of a variety of species. Peripheral administration of bremelanotide activates the mPOA and other hypothalamic and limbic regions of the brain involved in sexual behavior, and may work by activating dopamine terminals in the mPOA. Conclusions To the extent that solicitations indicate the desire of female rats to engage in sexual activity, bremelanotide appears to possess the behavioral, pharmacological, and neuroanatomical specificity required of a drug in the treatment of hypoactive sexual desire disorders.

Neuroanatomical distribution of the melanocortin-4 receptors in male and female rodent brain

“…These suggest that the MPOA may contain circuits which are facilitatory for appetitive sexual behaviors and inhibitory for lordosis. Microinjection of bremelanotide in the MPOA increases selectively female solicitations, without affecting lordosis (Gelez et al, 2006;Pfaus et al, 2007). This set of data suggests that the facilitatory role of the MPOA on female proceptive behaviors might be mediated by MC4-R. Another argument in favour of the critical role of MPOA MC4-R in female sexual desire is that MC4-R-positive neurons are largely more abundant in the MPOA than in the VMH, the main site of lordosis control, and interestingly bremelanotide microinjection into the MPOA enhances female proceptive behaviors and has no effect when injected in the VMH (Gelez et al, 2006).…”

“…Indeed, bremelanotide and melanotan-II (MT-II), two a-MSH analogs that non-selectively activate MCRs, increase female proceptive behaviors, such as solicitations and hops and darts, without modifying consummatory components such lordosis Rossler et al, 2006). This facilitatory effect of bremelanotide is blocked by a selective MC4-R antagonist, emphasizing the role of MC4-R in the control of female sexual motivation (Pfaus et al, 2007). Bremelanotide also positively affects sexual desire and arousal in premenopausal women suffering from sexual arousal disorder (Diamond et al, 2006;Safarinejad, 2008).…”

Neurobiology of Sexual Desire

“…The effectiveness of systemic melanocortin-II and bremelanotide to stimulate sexual desire in female rats has been replicated following infusions to the lateral ventricles of the brain and following infusions directly to the medial preoptic area (Pfaus et al, 2007). Interestingly, systemic administration of bremelanotide stimulates dopamine release selectively in the medial preoptic area, and its effect on solicitations is blocked by coadministration of a selective melanocotin receptor 4 antagonist or D1 antagonist (Pfaus et al, 2007). This suggests that melanocortins act presynaptically to increase dopamine release in the medial preoptic area and that such release acts on D1 receptors there to facilitate sexual desire.…”

Sexual dysfunction in women: What can urologists contribute?

“…Pfaus et al [42] reviewed the agent bremelanotide, an analogue of the naturally occurring peptide α-melanocyte-stimulating hormones. Bremelanotide has been studied in the preclinical context in female rats.…”