(033) Examining the Neuroanatomical Basis of Bremelanotide, a Drug for Low Sexual Desire in Women

Abstract

Abstract Introduction Low sexual desire is a commonly reported and often distressing form of sexual dysfunction in women. Characterized by diminished interest in sex, disinclination to initiate sex, and a loss of pleasure during sex, disorders of sexual desire among women are not only poorly understood from a psychological perspective, but also in terms of their underlying neurobiology. The drug bremelanotide, trade name Vyleesi, was approved by the FDA in 2019 to treat hypoactive sexual desire disorder in women. The drug is a synthetic analogue of the melanocortin receptor (MCR) agonist alpha-MSH and thus thought to bind to the melanocortin-4 receptor (MC4R) in the brain. However, despite its FDA approval, few preclinical studies or clinical trials have been performed on the drug. Objective We attempted to elucidate bremelanotide’s central nervous system effects in an established rodent model of female sexual behavior. Methods Female Syrian hamsters underwent 0, 2 or 5 weeks of sexual conditioning in the conditioned place preference apparatus, a validated model that is designed to test the rewarding properties of sexual behavior. Some hamsters that were conditioned for 2 weeks were also given a subcutaneous injection of bremelanotide. After the sexual conditioning experiment, brains were collected for assessment of MC4R expression in the striatum. mRNA expression of dopamine-1 and 2 receptors and MC4R were carried out using Syrian hamster customized RNAscope probes. Results Analysis of behavior data indicated the longer (5-week) sexual conditioning period was most effective for increasing responses indicative of reward, though the shorter (2-week) period also increased reward. However, neither the low dose nor high dose of bremelanotide increased reward responding as compared to control hamsters. Further, no brain changes in MC4R expression in the striatum were detected as a function of either sexual experience or bremelanotide treatment. MC4R was not co-expressed with dopamine-1 or dopamine-2 receptors in the nucleus accumbens or dorsal striatum. Conclusions Bremelanotide did not increase responding indicative of reward derived from sex in the female Syrian hamster model. Given that MC4R expression was unaffected by sexual experience and/or bremelanotide, our findings did not provide evidence that the drug acts via an MC4R-related mechanism in the central nervous system. MC4R was also not co-expressed with dopamine-1 or 2 receptors, suggesting the MC4R may instead be expressed by interneurons in the striatum. Despite our lack of evidence to support bremelanotide’s efficacy in animals, limitations of the rodent model of female sex behavior include the obvious psychosocial aspects of human sexuality that cannot be replicated. Further research is warranted to clarify bremelanotide’s mechanism of action. Disclosure No