Sexual Motivation and Sexual Reward in Male Rats are Attenuated by the Gonadotropin-Releasing Hormone Receptor Antagonist Degarelix

Background Preclinical studies that have examined the effects of androgen deprivation therapies (ADTs) on sexual outcomes have either relied on a surgical castration model of ADTs or have largely focused on consummatory sexual behaviors. Aim The aim of this study was to examine the effects of a single administration of the gonadotropin-releasing hormone receptor antagonist, degarelix, on sexual incentive motivation (SIM), sexual reward, consummatory sexual behaviors, anxiety-like behavior, and androgen receptor signaling in male rats, and to determine if sexual stimulation attenuates the effects of degarelix on SIM. Methods Male rats were treated with degarelix, or vehicle, and half of the rats in each condition were briefly exposed to a sexually receptive female immediately before SIM trials (experiment 1). Rats treated with degarelix or vehicle were also given a sex-conditioned place preference test (experiment 2A), weekly mating tests (experiment 2B), and an elevated zero maze test (experiment 3). Androgen-sensitive tissues were excised upon completion of testing. Outcomes SIM was indicated by the percentage of time spent near a sexually receptive female on the SIM tests. The percentage of time spent in the chamber of a conditioned place preference maze associated with sexual experience was indicative of sexual reward. The percentage of trials in which a mount, intromission, and ejaculation occurred was indicative of copulatory ability. Sexual performance was characterized by the average latencies to first exhibit these behaviors, as well as the average frequency of these behaviors. Anxiety-like behavior was indicated by the percentage of time in the open zones of an elevated zero maze. Relative weights of the seminal vesicles and bulbourethral glands were used to quantify androgen activity. Results Rats treated with degarelix exhibited lower levels of SIM. In rats treated with degarelix, contact with a female immediately before SIM testing increased activity, but not SIM. Treatment with degarelix reduced the rewarding aspects of sexual behavior, as well as most aspects of copulatory ability and sexual performance. Degarelix treatment reduced androgen signaling, but did not impact anxiety-like behavior. Clinical Implications The behavioral side effects associated with the use of degarelix may be restricted to sexual behaviors. Strengths & Limitations Strengths include the objective measurement of sexual behaviors. The study is limited in that only one ADT was examined. Conclusion These findings serve as an extension of previous preclinical studies as they indicate that gonadotropin-releasing hormone receptor antagonism in male rats also attenuates sexual motivation and sexual reward, in addition to copulatory ability and sexual performance. Hawley WR, Kapp LE, Green PA, et al. Sexual Motivation and Reward in Male Rats are Attenuated by the Gonadotropin-Releasing Hormone Receptor Antagonist Degarelix. J Sex Med 2021;18:240–255.