Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist
Abstract
Disorders of sexual desire affect an estimated 30% of women in North America and Europe, with etiologies based on interpersonal, personal, and physiological factors. There are currently no pharmacological agents approved for use in the treatment of female sexual dysfunction. This is due, in part, to a focus on the effects of experimental drugs on reflexive components of sexual behavior, such as lordosis (lower back curve), in animal models. Here we report that PT-141, a peptide analogue of ?-melanocyte-stimulating hormone (Melanotan 2) that binds to central melanocortin receptors, selectively stimulates solicitational behaviors in the female rat. This occurs without affecting lordosis, pacing, or other sexual behaviors. PT-141 did not cause generalized motor activation, nor did it affect the perception of sexual reward. A selective pharmacological effect on appetitive sexual behavior in female rats has not been reported previously, and indicates that central melanocortin systems are important in the regulation of female sexual desire. Accordingly, PT-141 may be the first identified pharmacological agent with the capability to treat female sexual desire disorders.
Neuropeptides derived from proopiomelanocortin (POMC), including ?-endorphin, corticotropin (ACTH), and ?-melanocyte-stimulating hormone (?-MSH or Melanotan 2), have pronounced effects on the sexual behavior of rats. In female rats, ?-MSH has been shown to facilitate or inhibit the sexually receptive posture lordosis depending on the hormonal status of the animals and whether they are in a low or high state of sexual receptivity, respectively. Estradiol increases ?-MSH levels in hypothalamic brain regions associated with female sexual behavior, suggesting that ?-MSH release may be one of several intermediaries of estrogen action. Recently, PT-141, a peptide analogue of ?-MSH, was reported to be erectogenic in men by an action believed to occur at central melanocortin type 3 or 4 receptors. Given the prevalence of sexual arousal and desire disorders in women and the lack of available pharmacological treatments, we asked whether PT-141 might facilitate appetitive aspects of sexual behavior in the female rat. Accordingly, the present study examined the dose–response effects of PT-141 on proceptive sexual behaviors, such as solicitation, hops and darts, and pacing, and receptive sexual behaviors, such as lordosis, in ovariectomized female rats tested under different hormone priming regimens in bilevel chambers* and unilevel pacing chambers.
Results
Treatment with PT-141 significantly increased proceptive solicitations in females primed with E+Por E alone (E+O) in bilevel chambers, but did not affect pacing, lordosis, or other measures of proceptivity such as hops and darts. The drug had even more pronounced effects in E+P-primed females that copulated in unilevel pacing chambers bisected by a four-hole divider. Treatment with the same doses of PT-141 significantly increased solicitations and hops and darts, but not lordosis. Females in unilevel chambers make more use of hops and darts as proceptive behaviors after solicitation; therefore, we expected this measure to increase concurrently with solicitations in the unilevel chambers. Females treated with the highest dose of PT-141 also attempted to mount the males. Female mounting of male rats is typically observed in E+P-primed females when they are paired with castrated or sexually sluggish males, and is considered a measure of proceptive sexual behavior. The latency to run away and return to the male after mounts or intromissions was not affected by PT-141. However, the latency to run away and return to the male after an ejaculation was increased significantly by PT-141. Ejaculation typically results in an increased return latency; thus, the effect of PT-141 appeared to enhance the impact of ejaculation.
Discussion
These results show a selective pharmacological enhancement of appetitive sexual behavior in female rats primed with E and P or with E alone. Solicitation and hops and darts are appetitive precopulatory sexual behaviors that female rats use to arouse males. Females that solicit and pace their copulatory contact receive vigorous copulatory stimulation from males at a desired interval, thus increasing the likelihood of pregnancy. The ability of PT-141 to enhance solicitation in two distinctive testing environments indicates that the effect is selective and stable, and suggests that central melanocortin systems are part of the neurochemical network that evokes appetitive sexual behavior in female rats. PT-141 shows high affinity for melanocortin receptor subtypes 1, 3, and 4, with no significant binding to 30 other neuropeptide or monoamine receptors found in the CNS. At present, the specific brain regions in which melanocortins may exert this effect are unknown. Considering that PT-141 also binds with high affinity to the melanocortin type 1 receptor, we cannot rule out a peripheral mechanism of action, especially for the increased return latency after ejaculation. However, PT-141's selective binding to melanocortin type 3 and 4 receptors within the CNS make a central action at hypothalamic and/or limbic structures that control appetitive sexual behavior likely. An increase in the activation of hypothalamic melanocortin systems induced by estrogen may also explain the peak in female-initiated sexual behaviors that occurs in many species, including humans, during ovulation.
Although the sexual behavior of rats is different from that of humans, the effects of pharmacological manipulations of appetitive and consummatory sexual behaviors are similar in male rats and men. This finding suggests that many aspects of the neurochemistry and neuroanatomy of male sexual responses are similar across species, and allows sexual responses of male rats to be used as models of human male sexual response. Behavioral concordance between female rats and women has received less attention. This is due, in part, to a concentration on the lordosis reflex as the defining characteristic of sexual behavior in female rats. Although lordosis is critical for vaginal intromission, and indicates that the female is receptive to such stimulation, it accounts for only one aspect of the behavioral pattern exhibited by females during copulation. Moreover, there is no human counterpart to lordosis as a measure of sexual receptivity. Other behaviors displayed by female rats during copulation are divided between solicitations and pacing, behaviors that allow females to initiate and regulate the timing of sexual contact. Indeed, hops and darts are also used by female rats to entice males to mount, and those behaviors were increased after PT-141 treatment. To the extent that appetitive measures of sexual activity in female rats are analogous to sexual desire in women, we conclude that PT-141 has the behavioral properties expected of a pharmacological aid in the treatment of sexual desire disorders.
Pfaus' research is centered around understanding how the brain is wired for sex. He and his research team study the hormonal and neurochemical mechanisms involved in sexual arousal, desire, reward (pleasure) and inhibition in rat models. His work in rats has elucidated basic neural and neurochemical pathways, and recent work has helped to illustrate how learning plays a critical role in sexual function and dysfunction, especially how experience with sexual pleasure feeds forward to generate desire. His work in humans focuses on subjective and objective measures of sexual desire in women and men and how different types of erotic stimuli alter such measures. He also examines the sexual functioning of individuals under stress or with anxiety disorders, and the effects of drugs abuse on sexual behavior in both animals and humans.
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