The elusive concept of sexual motivation: can it be anchored in the nervous system?

Sexual motivation is an abstract concept referring to the mechanisms determining the responsivity to sexually relevant stimuli. This responsivity determines the likelihood of producing a sexual response and the intensity of that response. Both responsivity to stimuli and the likelihood of making a response as well as the intensity of response are characteristics of an individual. Therefore, we need to assume that the concept of sexual motivation materializes in physiological mechanisms within the individual. The aim of the present communication is to analyze the requisites for the endeavor to materialize sexual motivation. The first requisite is to provide an operational definition, making the concept quantifiable. We show that parameters of copulatory behavior are inappropriate. We argue that the intensity of sexual approach behaviors provides the best estimate of sexual motivation in non-human animals, whereas the magnitude of genital responses is an exquisite indicator of human sexual motivation. Having assured how to quantify sexual motivation, we can then proceed to the search for physiological or neurobiological underpinnings. In fact, sexual motivation only manifests itself in animals exposed to appropriate amounts of gonadal hormones. In female rats, the estrogen receptor α in the ventrolateral part of the ventromedial nucleus of the hypothalamus is necessary for the expression of sexual approach behaviors. In male rats, androgen receptors within the medial preoptic area are crucial. Thus, in rats sexual motivation can be localized to specific brain structures, and even to specific cells within these structures. In humans, it is not even known if sexual motivation is materialized in the brain or in peripheral structures. Substantial efforts have been made to determine the relationship between the activity of neurotransmitters and the intensity of sexual motivation, particularly in rodents. The results of this effort have been meager. Likewise, efforts of finding drugs to stimulate sexual motivation, particularly in women complaining of low sexual desire, have produced dismal results. In sum, it appears that the abstract concept of sexual motivation can be reliably quantified, and the neurobiological bases can be described in non-human animals. In humans, objective quantification is feasible, but the neurobiological substrate remains enigmatic.

Being friendly: paced mating for the study of physiological, behavioral, and neuroplastic changes induced by sexual behavior in females.

Paced mating in rats is an experimental condition that allows the evaluation of sexual behavior in a way that closely resembles what occurs in seminatural and natural conditions enabling the female to control the rate of the sexual interaction. In conventional non-paced mating tests, females cannot escape from male approaches, which may lead to an unrewarding overstimulation. Paced mating is an alternative laboratory procedure that improves animal welfare and has a higher ethological relevance. The use of this procedure contributed to the identification of physiological and behavioral factors that favor reproduction. Paced mating includes motivational and behavioral components differentiating quantitative and qualitative characteristics that are critical for the induction of the rewarding properties of mating. These positive consequences ensure that the behavior will be repeated, favoring the species' survival. Sexual reward is an immediate consequence of paced mating, mediated mainly by the endogenous opioid system. Paced mating also induces long-lasting neuroplastic changes, including gene expression, synthesis of proteins, and neurogenesis in sex-relevant brain areas. The interest in paced mating is growing since the complexity of its elements and consequences at different levels in a laboratory setting resembles what occurs in natural conditions. In this review, we analyze the classic studies and recent publications demonstrating the advantages of using paced mating to evaluate different aspects of sexual behavior in females.

Sexual Incentive Motivation and Copulatory Behavior in Male Rats Treated With the Adrenergic α2-Adrenoceptor Agonists Tasipimidine and Fadolmidine: Implications for Treatment of Premature Ejaculation.

BACKGROUND: Premature ejaculation is the most common sexual dysfunction in young men, and it often leads to reduced relationship satisfaction and quality of life. AIM: To determine the role of central and peripheral α2-adrenoceptors in the control of ejaculation and sexual incentive motivation in rats. METHODS: Sexual incentive motivation was studied in a large arena in which a male subject could choose between approaching and remaining close to a sexually receptive female or another male. Sexual behavior was studied in standard observation cages in which a male was allowed to freely interact with a receptive female for 30 minutes. Two highly selective agonists at the α2-adrenoceptors, tasipimidine and fadolmidine, were administered before the tests. Low peripheral doses of fadolmidine have been reported to have effects mainly outside of the central nervous system, whereas at large doses also the central effects are evident. OUTCOMES: The time spent close to the receptive female in relation to the time spent with the male and measures of ambulatory activity were obtained from the test for sexual incentive motivation, while the habitual parameters of sexual behavior were recorded with the copulation test. RESULTS: Tasipimidine prolonged ejaculation latency and the interintromission interval at the dose of 200 µg/kg when data from fast-ejaculating rats were used. No other sexual parameter was modified. A dose of 100 µg/kg was ineffective. There was no consistent effect on sexual incentive motivation, although modest sedation was observed. Fadolmidine, a drug that does not easily penetrate the blood-brain barrier, had no effect on sexual incentive motivation at any of the doses used (3, 30, and 100 µg/kg). The largest dose had clear sedative effects. The lower doses had no systematic effect on sexual behavior, not even when only fast or very fast ejaculating males were analyzed. CLINICAL TRANSLATION: The findings are relevant to the search for treatments for premature ejaculation that are specific enough to selectively delay ejaculation. STRENGTHS & LIMITATIONS: The procedures used here are standard in the field and yield the most reliable data. Whether the effects observed in male rats are directly transferrable to men can only be determined through clinical studies. CONCLUSION: The observation that drugs acting at central but not peripheral α2-adrenoceptors prolong ejaculation latency without affecting any other parameter of sexual behavior or sexual incentive motivation suggests that this kind of drug may be suitable for treating premature ejaculation. Jyrki L., Elisa V.-A., Xi C., et al. Sexual Incentive Motivation and Copulatory Behavior in Male Rats Treated With the Adrenergic α2-Adrenoceptor Agonists Tasipimidine and Fadolmidine: Implications for Treatment of Premature Ejaculation. J Sex Med 2021;18:1677-1689.

Sexual behavior in rodents: Where do we go from here?

Hormones and Behavior was first published 50 years ago including some articles related to the hormonal regulation of sexual behavior in different species. Since then, this research field has produced outstanding discoveries that have contributed to our understanding of the control of sexual behavior. The refinement of classical techniques and the development of new experimental tools has opened the door to a new era of research that will allow us to understand different aspects of sexual behavior. It would also expand the possible extrapolation from animal models to understand human sexuality and its dysfunctions. In this review, we summarize some of the most recent findings about sexual behavior in both sexes including the refinement of classical methods of study with new approaches and questions as well as the development of new methods trying to explain mechanisms of action on motivational and consummatory elements of mating behavior. We also reviewed other aspects that modulate sexual behavior such as attractivity, olfactory signals and learning which model mate selection. Additionally, we described studies demonstrating that sexual behavior induces permanent brain modifications in neuronal circuits. Finally, we briefly describe recent contributions on animal models of human sexuality dysfunctions which, although with their own limitations, are under continuous refining.

Hormones and the Coolidge effect.

The Coolidge effect is the renewal of sexual behavior after the presentation of a novel sexual partner and possibly occurs as the result of habituation and dishabituation processes. This re-motivation to copulate is well studied in males and is commonly related to sexual satiety, which involves several neurobiological changes in steroid receptors and their mRNA expression in the CNS. On the other hand, there are few reports studying sexual novelty in females and have been limited to behavioral aspects. Here we report that the levels of rat proceptive behavior, a sign of sexual motivation, declines after 4 h of continuous mating, particularly in females that were unable to regulate the time of mating. Such reduction was not accompanied by changes in lordosis, suggesting that they were not due to the vanishing of the endocrine optimal milieu necessary for the expression of both components of sexual behavior in the female rat. These and previous data support important differences between sexual behavior in both sexes that would result in natural divergences in the Coolidge effect expression. We here also review some reports in humans showing peculiarities between the pattern of habituation and dishabituation in women and men. This is a growing research field that needs emphasis in female subjects.

Reduced Lordosis and Enhanced Aggression in Paced and Non-Paced Mating in Diabetic Female Rats.

BACKGROUND: Clinical studies have shown altered sexual function in people with diabetes; basic science studies, using the streptozotocin (STZ)-induced animal model of type 1 diabetes mellitus (DM1), have consistently reported decreased sexual behavior in hyperglycemic female animals, but features of sexual motivation and aggressive behavior have not been explored in these animals. AIM: To study several parameters that denote sexual motivation in STZ-treated female rats and to compare behavioral features of sexual behavior and aggression in non-paced mating (NPM) and paced mating (PM) conditions. METHODS: DM1 was induced by injecting STZ (diluted in citrate buffer) at a dose of 50 mg/kg intraperitoneally over 2 consecutive days into ovariectomized Wistar rats. 10 days later, female rats were treated with estradiol benzoate (10 µg, -24 hours) and progesterone (3 mg, -4 hours); their sexual behavior (including lordosis quotient, lordosis intensity, and proceptivity) and aggression were evaluated under NPM and PM conditions. Body weight, blood glucose levels, and spontaneous ambulatory activity also were measured. A group of STZ-treated animals was administered a long-acting insulin analogue (glargine) every 12 hours for 8 days, and their sexual and aggressive behaviors were evaluated in NPM. OUTCOMES: We quantified body weight, blood glucose level, spontaneous ambulatory activity, and sexual and aggressive behaviors in NPM and PM; the time the female rats spent interacting with the male rat or in the male rat's chamber also was registered in PM. RESULTS: Compared with controls, STZ-treated ovariectomized rats lost body weight, had increased blood glucose levels, and had unchanged spontaneous ambulatory activity. In the PM and NPM conditions, animals showed decreased lordosis quotient and lordosis intensity, increased aggression, and unaltered proceptivity, although in NPM the effects of STZ treatment on aggression were more drastic and were completely prevented by insulin. In PM no differences were found between diabetic and control female rats in the time interacting with the male rat or in the male rat's chamber. CLINICAL TRANSLATION: These findings support the observation of increased prevalence of sexual dysfunctions and aggression in the clinical setting of DM1. STRENGTHS AND LIMITATIONS: The main strength of this study is that it analyzed sexual behavior under PM and NPM conditions and aggression in STZ-treated female rats. Its main limitations are that the model of DM1 represents only 10% of the affected population and that no specific treatment is proposed for the sexual dysfunctions. CONCLUSION: These results suggest that STZ-treated rats have decreased sexual receptivity in NPM and PM, accompanied by increased aggressiveness in NPM. Hernández-Munive AK, Rebolledo-Solleiro D, Ventura-Aquino E, Fernández-Guasti A. Reduced Lordosis and Enhanced Aggression in Paced and Non-Paced Mating in Diabetic Female Rats. J Sex Med 2018;15:124-135.

Animal Models in Sexual Medicine: The Need and Importance of Studying Sexual Motivation.

INTRODUCTION: Many different animal models of sexual medicine have been developed, demonstrating the complexity of studying the many interactions that influence sexual responses. A great deal of effort has been invested in measuring sexual motivation using different behavioral models mainly because human behavior is more complex than any model can reproduce. AIM: To compare different animal models of male and female behaviors that measure sexual motivation as a key element in sexual medicine and focus on models that use a combination of molecular techniques and behavioral measurements. METHODS: We review the literature to describe models that evaluate different aspects of sexual motivation. MAIN OUTCOME MEASURES: No single test is sufficient to evaluate sexual motivation. The best approach is to evaluate animals in different behavioral tests to measure the motivational state of the subject. RESULTS: Different motivated behaviors such as aggression, singing in the case of birds, and sexual behavior, which are crucial for reproduction, are associated with changes in mRNA levels of different receptors in brain areas that are important in the control of reproduction. CONCLUSION: Research in animal models is crucial to understand the complexity of sexual behavior and all the mechanisms that influence such an important aspect of human well-being to decrease the physiologic and psychological impact of sexual dysfunctions. In other cases, research in different models is necessary to understand and recognize, not cure, the variability of sexuality, such as asexuality, which is another form of sexual orientation.

An unknown male increases sexual incentive motivation and partner preference: Further evidence for the Coolidge effect in female rats.

The Coolidge effect is the resumption of copulatory behavior induced by a novel sexual partner that has been reported in several species. The term is also used in males when they resume mating when exposed to an unknown receptive female after they have reached sexual exhaustion. Only few studies have evaluated the Coolidge effect in females. In the present study we further evaluated this possibility using the sexual incentive motivation (SIM) and the partner preference (PP) tests. Ovariectomized rats were hormonally primed and allowed to mate for 1h controlling the sexual interaction (paced mating) or in a condition where they were unable to pace the sexual encounters. In the SIM and PP tests, females were exposed to the male with whom they had mated before (known male) or with an unknown, sexually experienced one (unknown male). Regardless whether they paced the sexual interaction, all females showed clear preference for the unknown male but females that paced the sexual contacts spent more time in the incentive zone of the unknown male than females that could not pace the sexual interaction. Similar results were observed in the PP test. Both groups of females spent more time in the compartment of the previously unknown male than in that of the known one, but received the same amount of sexual stimulation, i.e., mounts, intromissions and ejaculations from both males. No preference was found when the females were tested in the SIM test between an unknown male and a sexually receptive female. The results further support the existence of a Coolidge effect in female rats that is more apparent if they pace the sexual interaction.

The antidepressants fluoxetine and bupropion differentially affect proceptive behavior in the naturally cycling female rat.

INTRODUCTION: Fluoxetine, like other selective serotonin reuptake inhibitors, inhibits women's sexual desire and female rats' sexual behavior. Bupropion produces pro-sexual effects in women with and without depression, and yohimbine increases men's and male rats' sexual motivation, but their effects on female rats' proceptivity are unknown. AIM: To investigate the effects of fluoxetine, bupropion, and yohimbine on proceptivity and receptivity in the naturally cycling female rat. METHODS: We studied the effect of chronic (minimum 14 days) fluoxetine (1.25 mg/kg, subcutaneous) and bupropion (5 mg/kg, intraperitoneal) and acute yohimbine (1 mg/kg, intraperitoneal) on sexual behavior of female rats selected in natural proestrus during an ejaculatory series. We also analyzed the effects of these treatments on locomotor activity. MAIN OUTCOME MEASURES: The main outcome measures were frequencies of hops/darts and ear wiggling, lordosis quotient and intensity, and locomotor activity. RESULTS: Fluoxetine inhibited ear wiggling and hopping/darting, while bupropion stimulated hopping/darting. These treatments did not modify the lordosis quotient and its intensity. Yohimbine did not change any aspect of female sexual behavior. At the doses and treatments used, fluoxetine and bupropion did not alter locomotor activity or disturb the length of the estrous cycle; however, yohimbine inhibited locomotor activity. CONCLUSIONS: The motivational components of female sexual behavior are more sensitive than the receptive components to the inhibitory actions of fluoxetine. Bupropion selectively stimulated hopping/darting, while yohimbine lacked an action on female sexual behavior.

Reduced proceptivity and sex-motivated behaviors in the female rat after repeated copulation in paced and non-paced mating: effect of changing the male.

The mating inhibition after repeated copulation (sexual satiety) and its re-commencement after changing the sexually active partner (Coolidge effect) are well recognized phenomena in males, but their occurrence in females is little explored. These two phenomena were compared in conditions when the female regulates copulation timing (pacing) and under non-paced mating. Female rats selected in proestrus copulated incessantly for 3 h with two different partners (for 90 min each), both of them sexually active and unknown for the female. During the entire test we recorded the hop/dart and ear wiggling frequencies and the lordosis quotient. In the pacing test we also registered the percentage of exits and the return latencies after mounts, intromissions and ejaculation within each copulatory series, the mean time the female spent in the neutral chamber and the number of crossings. In the non-paced mating situation there was a reduction in ear wiggling and hop/darting frequencies after 3 h of constant copulation. In the paced mating condition, also by the end of the test, the female spent more time in the neutral compartment and showed fewer crossings to the male's zone. Only when the female regulated mating, the change of the male provoked an increased hop/darting frequency accompanied by a reduced percentage of exits from the male's chamber after an intromission and in the time in the neutral compartment. These changes were not associated with alterations in receptivity, which was maximal along the test. Data are discussed by comparing the mating conditions and the sex differences in the effect of repeated copulation and partner replacement.