There has been an extensive search for efficient pharmacological treatment of female sexual interest/arousal disorder and other sexual dysfunctions. However, available treatments have met limited success, except for the drugs used for treating erectile deficiency. A possible reason for this may be that both the preclinical and clinical evaluation of treatment effects have been inadequate. The present literature review shows that the intensity of sexual approach behaviors in non-human animals appears to be predictive of clinical effect whereas the traditional studies of copulatory behaviors and associated motor patterns have questionable predictive power regarding effects on human sexual desire. In clinical studies, it is essential to include the unconscious components of sexual motivation in any approach to its quantification. This basic fact is incompatible with the use of self-reports for evaluating treatment effects on motivation. Genital responses to sexual incentives are automatic and therefore outside of volitional control and can, therefore, provide unbiased estimates of the intensity of sexual motivation. These responses may be objectively quantified. Tests for implicit sexual motivation must also be used for capturing unconscious mental components. Including the unconscious components of sexual motivation as well as of objective measures of genital responses in clinical studies may improve evaluations of the effectiveness of drug treatment of low sexual interest/arousal disorder. In preclinical studies, predictive validity can be improved by quantifying sexual approach behaviors rather than copulatory behavior. The paradigm shift suggested here may finally allow for the discovery of efficient treatments for some sexual dysfunctions.

Circulating testosterone is easily aromatized to estradiol and reduced to dihydrotestosterone in target tissues and elsewhere in the body. Thus, the actions of testosterone can be mediated either by the estrogen receptors, the androgen receptor or by simultaneous action at both receptors. To determine the role of androgens acting at the androgen receptor, we need to eliminate actions at the estrogen receptors. Alternatively, actions at the androgen receptor itself can be eliminated. In the present review, I will analyze the specific role of androgen receptors in male and female sexual behavior as well as in aggression. Some comments about androgen receptors and social recognition are also made. It will be shown that there are important differences between species, even between strains within a species, concerning the actions of the androgen receptor on the behaviors mentioned. This fact makes generalizations from one species to another or from one strain to another very risky. The existence of important species differences is often ignored, leading to many misunderstandings and much confusion.

In self-report questionnaires, men report higher scores than women on variables such as desire for sex, frequency of sexual thoughts, number of sex partners, etc. Based on this, men are considered to have a higher level of sexual motivation than women. However, retrospective self-reports may be unsuitable for estimations of the inherent level of sexual motivation. We review data on automatic (unconsciously controlled) responses and measures of implicit motivation during exposure to sexual stimuli. These responses and measures are inaccessible to willful manipulations and make it possible to determine whether the sex difference in answers to questionnaires is replicated when volitional response manipulations are unlikely. We complement the human data with observations from some rodent and non-human primate species. The attentional resources allotted to stimuli with sexual relevance as well as genital responses to such stimuli are similar in men and women. Measures of implicit motivation also fail to detect any sex difference. Finally, the frequency of masturbation is superior in female infants before the age at which social expectations begin to determine behavior. Neither in rodents nor in non-human primates is there any clear-cut evidence for sex differences in motivation. It seems that males and females are similar with regard to the intensity of sexual motivation. The responses to questionnaires may be affected by social learning of sexual scripts and/or the inferior quality of sexual experiences in women, among other things.

In recent years, the Food and Drug Administration approved two drugs for the treatment of hypoactive sexual desire disorder in premenopausal women which have been tested in preclinical tests with positive effects on some appetitive sexual behavior in female rats. Some years after their commercial release, the effectiveness of both drugs in women is not clear. In the present chapter, we present some considerations regarding preclinical studies of copulatory behavior, most of them conducted in female rats. Although knowledge of the neurobiological basis of copulatory behavior in the female rat is still growing, the extent to which these findings might be applied to women’s sexuality is unknown. On the other hand, sexual response in women is flexible and less hormone-dependent compared with men. Moreover, sociocultural factors deeply influence sexuality in women, and they might contribute to the development of sexual dysfunctions. Additionally, the kind of model that better describes sexual response in women seems to be individual and fluctuating. We briefly mentioned some of the most used methods for measuring genital arousal, putting out the need for developing better strategies to get objective and replicable results. We conclude that the contribution, if any, of animal models of sexual response in female rodents is modest. After the questionable approval and the lack of efficacy of drugs to treat sexual desire issues, it is necessary to realize that the more we understand the female sexual responses, developing better ways to evaluate them, the more we might explain, and eventually treat their dysfunctions.

The generalized social concern with sexual harassment and nonconsensual sex makes it imperative to incorporate notions of consent in any analysis of human sexual interactions. Such interactions follow an ordered sequence of events, starting with the perception of a sexual incentive, followed by an approach to it, genital interaction, and eventually orgasm. Consent from the partner is needed at every stage. At some points in this chain of events, the individuals involved make cognitive evaluations of the context and predictions of the likelihood for obtaining consent for proceeding to the next phase. Processes such as communication of consent or lack thereof, sexual decision making, and interpretation of cues emitted by the partner are decisive. Increased sexual motivation may influence these processes. However, available data make it possible to ascertain that enhanced motivation has no, or at most minor, effects, thereby invalidating the old assumption that heightened sexual motivation leads to impaired control.

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.

The low replicability of scientific studies has become an important issue. One possible cause is low representativeness of the experimental design employed. Already in the 1950's, Egon Brunswick pointed out that experimental setups ideally should be based on a random sample of stimuli from the subjects' natural environment or at least include basic features of that environment. Only experimental designs satisfying this criterion, representative designs in Brunswikian terminology, can produce results generalizable beyond the procedure used and to situations outside the laboratory. Such external validity is crucial in preclinical drug studies, for example, and should be important for replicability in general. Popular experimental setups in rodent research on non-human animals, like the tail suspension test or the Geller-Seifter procedure, do not correspond to contexts likely to be encountered in the animals' habitat. Consequently, results obtained in this kind of procedures can be generalized neither to other procedures nor to contexts outside the laboratory. Furthermore, many traditional procedures are incompatible with current notions of animal welfare. An approximation to the natural social and physical context can be provided in the laboratory, in the form of a seminatural environment. In addition to satisfy the basic demands for a representative design, such environments offer a far higher level of animal welfare than the typical small cages. This perspective article will briefly discuss the basic principles of the generalizability of experimental results, the virtues of representative designs and the coincidence of enhanced scientific quality and animal welfare provided by this kind of design.

Sexual behavior is, by necessity, sexually dimorphic. Males transfer sperm to females, whereas females receive sperm from males. Discussions of sex differences in copulatory behavior are consequently trivial. However, the behaviors associated with copulation, for example mate choice or postcopulatory reactions, may well be similar in males and females. Such differences, even subtle, are far easier to observe in seminatural environments than in the standard laboratory cage. We will present examples of the use of seminatural environments in insects and rodents. Even though most studies of insect sexual behavior are performed in relatively simple laboratory procedures, there are also some studies performed in natural or seminatural conditions. We briefly describe the most common procedures used and mention the main results. It is noteworthy that insect studies focus on sexual approach behaviors, particularly the role of visual and olfactory stimuli in mate location. The actual copulatory behavior, i.e., how gametes are transferred from one individual to another, seems to be of less interest. The sexual behavior of rats has traditionally been studied in heterosexual pairs, despite the fact that they often copulate in groups. Nevertheless, data obtained in the simplified environment have advanced knowledge of the endocrine and neurobiological control of sex behavior in a quite spectacular way. The understanding of the dynamics of the sexual interaction and the possible function of the many peculiarities of rat sexual behavior has not advanced to a similar degree. Studies in seminatural environments may provide valuable data concerning sociosexual interactions and how such interactions are modified by contextual events. Furthermore, observations made in an environment, which incorporates the basic features of rats’ natural habitat, offer some external validity. This is of importance when we want to generalize our results to contexts outside the laboratory, and it becomes of paramount important when we want to make inferences about behavior in other species, for example the human. We offer here a detailed description of an environment designed for studies of group-living rats, with notes on the observation procedure and the analysis of the large quantity of data generated in the environment.

In sexually reproducing species, male and female gametes fuse to generate offspring. Behavioral patterns have evolved that bring male and female gametes into physical contact. These behaviors range from stereotyped coordinated reciprocal movements displayed by females and males in animals with external fertilization (most fishes and amphibia), to a wide variety of behaviors in animals with internal fertilization. We present an overview of some of the few species for which behavioral data are available. Copulatory behavior in mammals comprises the execution of mounting of the male onto the female’s rump, intravaginal penile insertion, and ejaculation. These events occur either sequentially within a single behavioral pattern or as a series of discrete mounts with or without intromission and ending with ejaculation. In many mammals, male pelvic thrusting at mounting (preinsertive thrusting) is necessary for stimulating the female to assume lordosis and for achieving penile insertion and ejaculation. Wide differences exist across species, however, in the number, sequence, and characteristics of mounting and intromission preceding ejaculation, and in the persistence of thrusting during penile insertion. Thus, intravaginal pelvic thrusting is one of the criteria proposed for classification of male copulatory patterns. In some species, accelerometric and polygraphic techniques have been used to generate detailed descriptions of the dynamic characteristics of motor patterns displayed during thrusting, including vigor, frequency, and rhythmicity. This methodology has allowed us to identify the occurrence of intravaginal thrusting during the ejaculatory behavioral pattern in the rat. We identified two types of ejaculatory responses, with differences in the dynamic organization of the pelvic thrusting train and in the duration of the intravaginal thrusting period preceding ejaculation. This technique also allowed us to identify a period of fast intravaginal thrusting associated with ejaculation in the guinea pig, golden hamster, and mouse. A summary of the neurophysiology and endocrinology of thrusting is provided for those species for which sufficient data are available. Finally, the possible adaptive significance of preinsertive and postinsertive thrusting is discussed.

Sexual motivation (desire) requires the simultaneous presence of an active central motive state and a stimulus with sexual significance. Once activated, sexual motivation leads to visceral responses and approach behaviors directed toward the emitter of the sexual stimulus. In humans, such behaviors follow cognitive evaluation of the context, including predictions of the approached individual's response. After successful approach and establishment of physical contact, manifest sexual activities may be initiated. Sexual interaction is associated with and followed by a state of positive affect in most animals, whereas aversive consequences may be experienced by humans. The affective reactions may become associated with stimuli present during sexual interaction, and these stimuli may thereby alter their incentive properties. Here we show how the incentive motivation model can be used to explain the origins and possible treatments of sexual dysfunctions, notably disorders of desire. We propose that associations formed between negative outcomes of sexual interaction and the salient stimuli, for example, the partner, underlies hypoactive desire disorder. Highly positive outcomes of sexual interaction enhance the incentive value of the stimuli present, and eventually lead to hyperactive sexual desire. Treatments aim to alter the impact of sexual incentives, mainly by modifying cognitive processes.

Sexual incentive stimuli activate sexual motivation and heighten the level of general arousal. The sexual motive may induce the individual to approach the incentive, and eventually to initiate sexual acts. Both approach and the ensuing copulatory interaction further enhance general arousal. We present data from rodents and humans in support of these assertions. We then suggest that orgasm is experienced when the combined level of excitation surpasses a threshold. In order to analyze the neurobiological bases of sexual motivation, we employ the concept of a central motive state. We then discuss the mechanisms involved in the long- and short-term control of that state as well as those mediating the momentaneous actions of sexual incentive stimuli. This leads to an analysis of the neurobiology behind the interindividual differences in responsivity of the sexual central motive state. Knowledge is still fragmentary, and many contradictory observations have been made. Nevertheless, we conclude that the basic mechanisms of sexual motivation and the role of general arousal are similar in rodents and humans.

One of the consequences of sexual behavior is reproduction. Thus, this behavior is essential for the survival of the species. However, the individual engaged in sexual behavior is rarely aware of its reproductive consequences. In fact, the human is probably the only species in which sexual acts may be performed with the explicit purpose of reproduction. Most human sexual activities as well as sex in other animals is performed with the aim of obtaining a state of positive affect. This makes sexual behavior important for wellbeing as well as for reproduction. It is not surprising, then, that sexual health has become an increasingly important issue, and that knowledge of the basic mechanisms controlling that behavior are urgently needed. The endocrine control of sexual behavior has been extensively studied, and although it is established that gonadal hormones are necessary, some controversy still exists concerning which hormone does what in which species. The brain areas necessary for sexual behavior have been determined in almost all vertebrates except the human. The medial preoptic area is crucial in males of all non-human vertebrates, whereas the ventromedial nucleus of the hypothalamus is important in females. Modulatory functions have been ascribed to several other brain areas.

Although rats are known to emit ultrasonic vocalizations (USVs), it remains unclear whether these calls serve an auditory communication purpose. For USVs to be part of communication, the vocal signals will need to be a transfer of information between two or more conspecifics, and with the possibility to induce changes in the behavior of the recipient. Therefore, the aim of our study was to investigate the role of USVs in adult rats’ social and non-social investigation strategies when introduced into a large novel environment with unfamiliar conspecifics. We quantified a wide range of social and non-social behaviors in the seminatural environment, which could be affected by subtle signals, including USVs. We found that during the first hour in the seminatural environment the ability to vocalize did not affect how quickly adult rats met each other, their overall social investigation behavior, their passive social behavior nor their aggressive behavior. Furthermore, the non-social exploratory behaviors and behaviors reflecting anxiety/stress-like states were also unaffected. These results demonstrated that a disability to vocalize did not result in significant disadvantages (or changes) compared to intact conspecifics regarding social and non-social behaviors. This suggests that other (multi)sensory cues are more relevant in social interactions than USVs.

Masculinization and feminization of rat sexual behavior has been supposed to occur during a short postnatal period. However, much data have made it evident that these processes may continue until adolescence. In the present study, we evaluated whether androgen treatment of females from postnatal day 20 and onwards could alter sexual motivation and behavior in a male direction. Juveniles were ovariectomized on day 20 and concurrently implanted with Silastic capsules containing either testosterone or dihydrotestosterone. Controls were implanted with an empty capsule. Tests for sexual incentive motivation and male sexual behavior were performed every fifth day when the females were between 50 and 75 days of age. At day 80, a test for female sexual behavior was performed. Females treated with testosterone approached a female sexual incentive far more than a male incentive, showing that sexual motivation had been changed in a male-like direction. Dihydrotestosterone had a similar, albeit smaller, effect. Females implanted with an empty capsule approached both incentives equally. Testosterone produced a high level of mounting behavior, whereas intromission-like behavioral patterns were rare and ejaculation-like behavior was absent. In the test for female sexual behavior, the testosterone-treated animals displayed a relatively high lordosis quotient, far above that displayed in females implanted with dihydrotestosterone or an empty capsule. It is concluded that treatment with an aromatizable androgen during the peripubertal-adolescent period masculinizes sexual motivation and partly sexual behavior. A non-aromatizable androgen weakly masculinize sexual motivation without enhancing male sexual behavior. It appears that simultaneous actions on androgen and estrogen receptors are needed for significant masculinization during the period studied here. Since the testosterone-treated females displayed lordosis, sexual behavior was not defeminized. In sum, these results suggest that sexual differentiation continues well into the peripubertal and adolescent periods.

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 alpha(2)-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 alpha(2)-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 mg/kg when data from fast-ejaculating rats were used. No other sexual parameter was modified. A dose of 100 mg/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 mg/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 inmale rats are directly transferrable tomen can only be determined through clinical studies. Conclusion: The observation that drugs acting at central but not peripheral alpha(2)-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. Incentive Copyright (C) 2021, International Society of Sexual Medicine. Published by Elsevier Inc. All rights reserved.

In classical rodent anxiety models, females usually display lower anxiety than males, whereas anxiety disorders are more prevalent in women. Perhaps this contradiction is caused by the use of behavioural models with low external validity. Therefore, we analysed immediate reactions to a sudden 90-dB white noise in a semi-natural environment. We observed mixed-sex groups of rats for the 60 seconds preceding noise onset and the first 60 seconds of exposure. White noise elicited fear-specific behaviours hiding alone and huddling. It also increased exploratory and ambulatory behaviours, although only in the burrow zone farthest from the open area. Thus, in a semi-natural environment, white noise enhanced motor activity as a product of fear-induced general arousal. Then, we compared male and female sexual, social, exploratory and anxiety-related behaviour, and found little sex difference. This absence of behavioural effect, also observed in other studies, might be a result of our study design, a familiar environment with an ecologically relevant social context. Fear and anxiety responses are modulated by oestrogens through the activation of oestrogen receptors alpha and beta. Thus, in a third part of out study, we analysed how treatment with either oil, oestradiol benzoate (EB), an agonist to the oestrogen receptor alpha (propylpyrazoletriol [PPT]) or beta (diarylpropionitrile [DPN]) influenced female behaviour. The effect of treatment was limited, both EB and PPT stimulated motor activity in the open area before white noise, probably because of sexual activity. PPT increased the probability of fleeing from the noise, and decreased the latency to do so, which is consistent with a pattern of anxiogenic properties found in previous studies. Contrary to reports in classical procedures, we failed to detect any effect of DPN on immediate fear reactions in a semi-natural environment.

Both male and female rats produce vocalizations in the presence of a potential sexual partner. In this study we evaluated the role of vocalizations in sociosexual behaviors in an ecologically valid procedure. Three males and four females were housed in a seminatural environment. In each group one or two males and females were devocalized and the other subjects were sham operated. Sociosexual interactions between males and females were recorded for a period of one hour when all four females were receptive so that the males had the choice to interact either with vocalizing or with silent females. Devocalized and sham operated males displayed very similar behavioral patterns. There was no difference in any of the male sexual behavior patterns nor in maleinitiated non-sexual social interaction. Female vocalizations do not contribute to the regulation of sociosexual interaction. Devocalized males received as much attention from females as sham operated males, with the exception of paracopulatory behavior with short duration which were more frequently directed towards the sham operated males than to the devocalized males. This was the case for both silent and vocalizing females. It appears, then, that devocalized males are inferior to sham males with regard to the capacity to induce female paracopulatory behaviors. However, this has no consequence for sexual interaction, since devocalized and sham male copulated equally. In sum, these data show that vocalizations play a very limited role in rat sociosexual behavior in a seminatural environment. Furthermore, this indicates that vocalizations have no evident function during copulatory interactions.

Editor's Note: This article has been retracted. Please see the retraction notice for more detail: https://www.nature.com/articles/s41443-020-0321-x