Sexual Behavior In Female Rats Research Articles

Kisspeptin administration may promote precopulatory behavior in male rats independently or supplementally to testosterone and contribute to proceptive behavior in female partners, reducing mating failure

Kisspeptin is a peptide that plays an important role through its effects on the hypothalamus-pituitary–gonadal (HPG) axis. It has also been implicated in sexual behavior. The present study investigated whether the relationship between kisspeptin and sexual behavior is independent of the HPG axis, i.e., testosterone. Sexual behavior was examined after the administration of kisspeptin to gonadally intact male rats and gonadectomized male rats that received testosterone supplementation. Other male rats were also observed for sexual behavior once a week from 2 to 5 weeks after gonadectomy and receiving kisspeptin for the sixth postoperative week. Sexual behavior in female rats serving as the partner for each male was also observed. Female rats were not administered kisspeptin in the present study. The results obtained showed that the administration of kisspeptin increased precopulatory behavior in gonadally intact male rats and gonadectomized male rats that received testosterone supplementation and proceptive behavior in their female partners. Precopulatory behavior in males and receptive behavior in females increased, while copulatory behavior in males and receptive behavior in females remained unchanged. Furthermore, the administration of kisspeptin increased precopulatory behavior in gonadectomized males, but did not affect receptive behavior in females. These results suggest that kisspeptin affected males independently and/or supplementally to testosterone, and also that changes in the presence of testosterone in males had an impact on proceptive behavior in their female partners. In conclusion, kisspeptin may involve an as-yet-unidentified neural pathway in sexual desire independently of the HPG axis.

The Effects of Chronic Asprosin Administration on Sense of Smell and Sexual Behavior in Female Rats

Introduction: Asprosin is an adipokine released from white adipose tissue during fasting and acts through the olfactory receptor. It is known that adipokines play roles in reproductive physiology in mammals. However, there are very few studies conducted on role of asprosin in reproductive functions. There are no studies on its relationship with sexual motivation. It was shown in the literature that administration of asprosin to male mice improves olfaction. It is also known that there is a strong correlation between smell and sexual desire. In view of this, it was hypothesized that chronic administration of asprosin would improve olfactory performance and increase sexual incentive motivation in female rats for male partners. Methods: This hypothesis was tested by applying the hidden cookie test, sexual incentive test, active research test, and sexual behavior test. The changes in serum hormone levels in female rats that chronically received asprosin were also measured and compared. Results: Chronic asprosin exposure increased olfactory performance, male preference ratio, male investigation preference ratio, activity index, and anogenital investigation behavior. Also, serum oxytocin and estradiol levels increased following chronic administration of asprosin in female rats. Conclusion: These data suggest that chronic administration of asprosin can result in increased sexual incentive motivation for opposite sex in female rats over increased olfactory performance and changes in reproductive hormones.

Double perinatal stress reduces the sexual response of adult female Wistar rats.

Early-life stress affects physiological development and produces changes in various aspects of emotional behavior. We sought to examine the effects of double perinatal stress (DPS)-a combination of prenatal systemic hypoxic-ischemic (HI) insults and repeated early maternal separation-on the estrus cycle and sexual behavior of adult rats. HI was induced by clamping the uterine arteries of pregnant rats for 45minutes on the 18th day of gestation (HI group). Sham control animals received laparotomy and anesthesia only. Pups were born at term. Maternal separation was performed from postnatal day 1 (P1) (P0 = day of birth) to P15. At P90, the sexual response of females in estrus was evaluated. Statistical analysis was performed using 2-way analysis of variance followed by Tukey's test. We considered the estrous cycle and sexual behavior of female rats submitted to DPS, as well as the influence of female behavior on the sexual response of male rats. Rats submitted to DPS showed a reduction in the lordosis quotient and in the lordosis rate, suggesting a reduction in female sexual receptivity. DPS female rats showed a reduction in the number of hops and darts and in the genital exploration time rate, suggesting a reduction in sexual proceptivity. In addition, males that interacted with DPS females showed a reduction in the number of ejaculations and in copulatory efficiency. Developing a deeper understanding of perinatal factors that affect adult female sexual response will allow for more effective interventions to prevent and treat such changes. On the other hand, the analysis of the sexual response allows assessing the quality of life and the general state of health. The development of animal models to investigate the environmental factors that interfere in the female sexual response may allow researchers to propose and test new therapeutic strategies. On the other hand, care must be exercised when interpreting animal data and extrapolating these results to estimate the possible effects of perinatal stressors on the human sexual response. Our results revealed that females subjected to DPS showed long-term effects on sexual behavior. In conclusion, managing stressors in prenatal life and early postnatal life can prevent problems in adult sexual life and improve overall health.

Immediate and Long-Term Effects of Tibial Nerve Stimulation on the Sexual Behavior of Female Rats

ObjectivesThere are limited treatment options for female sexual dysfunction (FSD). Percutaneous tibial nerve stimulation (PTNS) has shown improvements in FSD symptoms in neuromodulation clinical studies, but the direct effects on sexual function are not understood. This study evaluated the immediate and long-term effects of PTNS on sexual motivation and receptivity in a rat model of menopausal women. Our primary hypothesis was that long-term PTNS would yield greater changes in sexual behavior than short-term stimulation. Materials and MethodsIn two experiments, after receiving treatment, we placed ovariectomized female rats in an operant chamber in which the female controls access to a male by nose poking. We used five treatment conditions, which were with or without PTNS and no, partial, or full hormone priming. In experiment 1, we rotated rats through each condition twice with behavioral testing immediately following treatment for ten weeks. In experiment 2, we committed rats to one condition for six weeks and tracked sexual behavior over time. We quantified sexual motivation and sexual receptivity with standard measures. ResultsNo primary comparisons were significant in this study. In experiment 1, we observed increased sexual motivation but not receptivity immediately following PTNS with partial hormone priming, as compared with priming without PTNS (linear mixed effect models; initial latency [p = 0.34], inter-interval latency [p = 0.77], nose poke frequency [p = 0.084]; eight rats). In experiment 2, we observed trends of increased sexual receptivity (linear correlation for weekly group means; mounts [p = 0.094 for trendline], intromissions [p = 0.073], lordosis quotient [p = 0.58], percent time spent with a male [p = 0.39], decreased percent time alone [p = 0.024]; four rats per condition), and some sexual motivation metrics (linear correlation for weekly group means; nose pokes per interval [p = 0.050], nose poke frequency [p = 0.039], decreased initial latency [p = 0.11]; four rats per condition) when PTNS was applied long-term with partial hormone priming, as compared with hormone-primed rats without stimulation. ConclusionsPTNS combined with hormone priming shows potential for increasing sexual motivation in the short-term and sexual receptivity in the long-term in rats. Further studies are needed to examine variability in rat behavior and to investigate PTNS as a treatment for FSD in menopausal women.

Effect of Music Exposure on Sexual Behavior of Female Rats

Background: The human limbic system is excited by music. The nervous system sends music signals converted into neural information by inner hair cells to the primary auditory area and limbic system. This activates genes that play a role in social and cognitive function. This study aims to prove the effect of music on physiological sexual behavior. Methods: The study was conducted on adult female Rattus norvegicus rats aged 2-3 months with a body weight of about 200 grams. The rats were exposed to the sound of music which divided into soft (Javanese), medium (Balinese gamelan), and loud (Dangdut tekno) music categories. The duration of exposure for each type of music is two hours in a row for seven days. During music exposure, rats' behavior in cages was recorded using CCTV. The test carried out is a normality test using the T-test (student's t-test). Results: A comparison test between treatment groups showed that all groups did not show differences in general behavior. For sexual behavior, the normality test showed that the Balinese group was the only abnormal group. The Piano group's sexual behavior was statistically the same as the control group. Conclusion: Exposure to Balinese gamelan showed an increase in sexual activity in female rats. Balinese gamelan music shows a relationship between music and limbic system activity, which is indicated by increased activity in the estrous phase. Keywords: emotion, limbic system, music, sexual activity

Adolescence and Postpartum: Two Life Periods to Deepen Our Understanding of the Complexity of Female Rat Sexual Behavior

The sexual behavior of the female rat has been extensively studied and used as a model for human female sexuality. The development of models that focus on sexual interaction from the female’s perspective has demonstrated the complexity of this behavior, in which motivational and affective aspects have great relevance. This review describes, from a historical perspective, some of the studies that have shed light on this complexity and presents the potential of two periods in the female’s life to expand our understanding of sexual behavior: adolescence and postpartum estrus. Cycling adolescent female rats can express sexual behavior even though some of the underlying circuitry is still developing. Therefore, this is an ideal time for studying the ontogeny of sexual behavior, the interaction of sexual and social motivations, and the neuroendocrine changes that lead to adult behavior. Female rats also show a fertile estrus a few hours after parturition. During this period, rats are simultaneously sexually and maternally motivated, making postpartum estrus an excellent model for exploring the interaction of these two social motivations. What we know so far about female sexual behavior in these unique periods of life reaffirms its richness and shows that much remains to be known.

Prenatal stress reduces heterotypical sexual behavior and inhibits homotypical sexual behavior in female rats: relationships with kisspeptin

We aimed to determine weight change over time and identify risk factors of critical weight loss among patients with nasopharyngeal carcinoma (NPC).In this retrospective study, we investigated weight change over time in 445 patients with NPC who underwent curative treatment. Logistic regression analysis was used to identify possible predictors of critical weight loss.The incidence of critical weight loss was 67.87%. The long-term monitoring demonstrated a rapid weight loss, especially in the first 2 months of treatment, which continued up to 5 months. Patients with critical weight loss did not regain weight until 3 years. Univariate analysis showed that the following factors were significantly associated with critical weight loss: lower pretreatment body mass index (BMI), tumor stage, subjective global assessment score, Eastern Cooperative Oncology Group (ECOG) score, and enteral tube feeding. Multivariate analysis showed four factors that were associated with a lower critical weight loss: pretreatment BMI < 18.5 kg/m2 (p < 0.001, 95% confidence interval [CI] = 0.25 [0.12–0.52]), early tumor stage (p = 0.004, 95% CI = 0.46 [0.27–0.79]), ECOG grade II (p = 0.006, 95% CI = 0.15 [0.04–0.51]), and early prophylactic percutaneous gastrostomy (PEG) tube feeding (p = 0.001, 95% CI = 0.26 [0.12–0.59]).Patients having NPC with critical weight loss showed a significantly rapid decline in their weight in the first 2 months; the weight was persistently less than the baseline value during a 36-month follow-up period. Patients with lower BMI, early-stage cancer, and early prophylactic PEG tube feeding had a significantly lower critical weight loss than those without the abovementioned characteristics.

II. Antidepressants and sexual behavior: Acute fluoxetine, but not ketamine, disrupts paced mating behavior in sexually experienced female rats

Female sexual dysfunction is both a symptom of depression and exacerbated by treatments for depression. Ketamine, a novel treatment for depression, has been shown to enhance, whereas fluoxetine has been shown to impair sexual motivation. Sexual experience leads to more robust partner preference and paced mating behavior in female rats. Whether acute ketamine and fluoxetine similarly affect sexual motivation and mating behavior in sexually experienced female rats is unknown. Sexually experienced female rats received 10 mg/kg i.p. of ketamine or saline vehicle (Experiment 1) or 10 mg/kg i.p. of fluoxetine or water vehicle (Experiment 2) 30 min before a 10-min no-contact partner preference test followed immediately by a 15-intromission paced mating test. Partner preference and paced mating behavior did not differ between ketamine- and saline-treated rats. In contrast, rats treated with fluoxetine spent significantly less time with either stimulus animal and were less active during the partner preference test than water-treated rats. Additionally, contact-return latency to ejaculation was significantly longer in fluoxetine-treated rats and they spent less time with the male during paced mating in comparison to water-treated rats. Thus, even with sexual experience, fluoxetine disrupts sexual function whereas ketamine has no detrimental effects on sexual behavior in female rats. A growing body of evidence suggests that ketamine is an encouraging new approach to treat depression particularly because it is not associated with sexual dysfunction.

Female rat sexual behavior is unaffected by perinatal fluoxetine exposure

Serotonin plays an important role in adult female sexual behavior, however little is known about the influence of serotonin during early development on sexual functioning in adulthood. During early development, serotonin acts as neurotrophic factor, while it functions as a modulatory neurotransmitter in adulthood. The occurrence of serotonin release, could thus have different effects on behavioral outcomes, depending on the developmental period in which serotonin is released. Because serotonin is involved in the development of the HPG axis which is required for puberty establishment, serotonin could also alter expression patterns of for instance the estrogen receptor ɑ (ERɑ).The aim of our study was to investigate the effects of increased serotonin levels during early development on adult female rat sexual behavior during the full behavioral estrus in a seminatural environment. To do so, rats were perinatally exposed with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10 mg/kg FLX) and sexual performance was tested during adulthood. All facets of female sexual behavior between the first and last lordosis (behavioral estrus), and within each copulation bout of the behavioral estrus were analyzed. Besides the length and onset of the behavioral estrus and the sexual behaviors patterns, other social and conflict behavior were also investigated. In addition, we studied the effects of perinatal FLX exposure on ERɑ expression patterns in the medial preoptic nucleus, ventromedial nucleus of the hypothalamus, medial amygdala, bed nucleus of the stria terminalis, and the dorsal raphé nucleus.The results showed that perinatal fluoxetine exposure has no effect on adult female sexual behavior. The behavioral estrus of FLX-females had the same length and pattern as CTR-females. In addition, FLX- and CTR-females showed the same amount of paracopulatory behavior and lordosis, both during the full behavioral estrus and the “most active bout”. Furthermore, no differences were found in the display of social and conflict behaviors, nor in ERɑ expression patterns in the brain. We conclude that increases in serotonin levels during early development do not have long-term consequences for female sexual behavior in adulthood.

The effects of 28-day early-life exposure to triphenyl phosphate (TPhP) on odor preference and sexual behavior in female rats.

Many chemical substances are detectable in house dust, and they are consequently taken into our bodies via the mouth and nose. Triphenyl phosphate (TPhP), a flame retardant that has an estrogen‐like effect in vitro, is present in house dust at high concentrations. Estrogen exposure during development has significant influences on reproductive behavior in rodents, and its effects persist until maturity. In the present study, we investigated the effect of early life exposure to TPhP on the reproductive behavior of female rats. Oral treatment with TPhP (25 or 250 mg/kg), ethinyl estradiol (EE; 15 μg/kg) as a positive control, or sesame oil as a negative control, were given to female rats (from birth to 28 days of age). The 8‐week‐old rats were bilaterally ovariectomized. At 12–15 weeks of age, the rats were subjected to odor preference and sexual behavior tests. In the odor preference test, the oil group showed significantly higher preference for male odor than female odor, but the low‐dose TPhP treatment group lost the preference for male odor, indicating a possible outcome of early life TPhP exposure on sexual recognition. In the sexual behavior test, both the EE and TPhP treatment groups displayed significantly less proceptive behavior. These results suggest that early life exposure to TPhP disturbs the normal sexual behavior of female rats.

Central Actions of 3α,5α-THP Involving NMDA and GABAA Receptors Regulate Affective and Sexual Behavior of Female Rats.

The neurosteroid, 5α-pregnan-3α-ol-20-one (known as “allopregnanolone” or 3α,5α-THP), is produced in the midbrain ventral tegmental area (VTA), independent of peripheral sources of progestogens, where it has potential actions at N-methyl-D-aspartate (NMDA) and GABAA receptors to facilitate rodent sexual behavior. Progestogens can also have anti-anxiety effects, but whether these involve actions of centrally-derived 3α,5α-THP or these receptors to support reproductively-relevant behavior is not well understood. We investigated the extent to which 3α,5α-THP’s actions via NMDA and/or GABAA receptors in the midbrain VTA influence reproductive behaviors. Estradiol-primed, ovariectomized/adrenalectomized (OVX/ADX) rats received midbrain VTA infusions of vehicle, an NMDA receptor blocker (MK-801; 200 ng), or a GABAA receptor blocker (bicuculline; 100 ng) followed by a second infusion of vehicle or 3α,5α-THP (100 ng). Reproductively-relevant behaviors were assessed: sexual (paced mating), anxiety-like (elevated plus maze), and social (partner preference, social interaction) behavior. Compared to vehicle, intra-VTA infusions of MK-801 exerted anxiolytic-like effects on elevated plus maze behavior and enhanced lordosis. Unlike prior observations in gonadally-intact rats, intra-VTA bicuculline had no effect on the behavior of OVX/ADX rats (likely due to a floor effect). Subsequent infusions of 3α,5α-THP reversed effects on lordosis and infusions of bicuculline inhibited 3α,5α-THP-facilitated lordosis. Thus, NMDA and GABAA receptors may act as mediators for reproductive behavioral effects of 3α,5α-THP in the midbrain VTA.

The reduction in sexual behavior of adult female rats exposed to immune stress in the neonatal period is associated with reduced hypothalamic progesterone receptor expression

PurposeWe examined the mechanism by which neonatal immune stress reduces the sexual behavior of female rats in adulthood. MethodsNeonatal female rats were randomly divided into 3 groups: control (n = 11), postnatal day 10 lipopolysaccharide (PND10LPS) (n = 23), and PND25LPS (n = 11) groups, which received intraperitoneal injections of LPS (100 μg/kg) or saline on PND10 and 25. Daily inspections of the vaginal opening (VO) were performed from PND27 to PND37. Thereafter, the frequency of estrus was assessed for 15 days. Female rats (at 11–12 weeks of age) were placed in a cage with male rats, and their sexual behavior was monitored for 30 min. The hypothalamic mRNA expression levels of factors related to sexual behavior were examined via real-time PCR. ResultsVO occurred later and the frequency of estrus was lower in the PND10LPS group compared to the control group. The number of lordosis behaviors and the total number of mounts performed by male partners were lower in the PND10LPS and PND25LPS groups than in the control group. Acceptability: The lordosis quotient and lordosis rating were lower in the PND10LPS group than in the control group. Proceptive behavior: the number of ear wiggling events was lower in the PND10LPS group than in the other groups, and the number of hops/darts was lower in the PND10LPS group than in the control group. The hypothalamic mRNA expression level of progesterone receptors (PR)A + B was lower in the PND10LPS group than in the control group, and the hypothalamic PRB mRNA expression level was lower in the PND10LPS and PND25LPS groups than in the control group. ConclusionNeonatal immune stress impeded sexual behavior and hypothalamic PR mRNA expression in female rats. Decreased progesterone activity in the hypothalamus might explain the reduction in sexual behavior seen in these rats.

The combination of mirtazapine plus venlafaxine reduces immobility in the forced swim test and does not inhibit female sexual behavior

IntroductionDepression is a psychiatric disorder with higher incidence in women. Among the most common and less investigated adverse effects of antidepressants are the female sexual dysfunctions. Up to one third of the patients fail to respond to antidepressants; therefore, more treatment alternatives are necessary. The combination of mirtazapine plus venlafaxine, known as “California Rocket Fuel” has shown to be an option for treatment-resistant depression. However, there are no reports of the effects of this combination in animal models and its action on female sexual behavior is unknown. AimTo analyze the effect of mirtazapine and venlafaxine alone or combined –given at doses with actions on the forced swim test- on female rat sexual behavior. MethodsMirtazapine (10, 20 or 40 mg/kg) and venlafaxine (15, 30 or 60 mg/kg) or their combinations (2.5/3.75, 5/7.5, 10/15 and 20/30 mg/kg mirtazapine and venlafaxine, respectively) were injected to sexually receptive female rats. We evaluated their effect on the forced swim test (FST). The doses that reduced immobility were tested on proceptivity and receptivity. ResultsMirtazapine (40 mg/kg) and venlafaxine (60 mg/kg), administered alone, or combined (mirtazapine, 5, 10 and 20 mg/kg plus venlafaxine, 7.5, 15 and 30 mg/kg) reduced immobility, but affected motor activity. However, the reduced locomotion after the lowest combination (5/7.5 mg/kg) was smaller. Mirtazapine at 40 mg/kg reduced proceptivity and receptivity, while 60 mg/kg venlafaxine only decreased proceptivity. The combination of 5/7.5 mg/kg mirtazapine and venlafaxine did not affect female sexual behavior. ConclusionsMirtazapine and venlafaxine exerted an effect in the FST, which was also evident when sub-effective doses of both antidepressants were combined. This combination also lacked adverse effects on female sexual behavior. The results suggest that “California Rocket Fuel” could be an effective antidepressant therapy with no adverse sexual effects in women.

Vaporized Cannabis differentially modulates sexual behavior of female rats according to the dose

Studies exploring the effect of compounds that modulate the endocannabinoid system on sexual behavior have yielded contradictory results. However, the effect of smoked Cannabis in women has been consistently associated with an increase in sexual drive. Therefore, it can be speculated that vaporized Cannabis will augment sexually motivated components of the sexual behavior of female rats. To test this hypothesis, we compared the sexual behavior of late-proestrous female rats in a bilevel chamber after vaporizing 0, 200 or 400 mg of Cannabis flowers (containing 18% of delta-9-THC and undetectable levels of cannabidiol) during 10 min. We found that both doses of Cannabis increased the duration of the lordosis response, whereas the highest dose also reduced the lordosis quotient of females. The lowest dose of Cannabis augmented the display of hops and darts without altering the expression of sexual solicitations of females, while the highest one did not affect the expression of hops and darts but reduced sexual solicitations. These effects were not accompanied by alterations of females' ambulatory behavior. The increment of the duration of lordosis response produced by both doses of Cannabis could be associated to a general effect of this drug in sensory processing, as can be an enhancement of females' sensory reactivity to male's stimulation. However, the reduction in the display of solicitations and lordosis in response to mounting observed in females exposed to the highest dose when compared to control and 200 mg of Cannabis groups indicates a reduction of sexual receptivity and motivation. This differential effect of vaporized Cannabis according to the dose employed, suggests that it modulates sexual behavior in a complex way, impacting neural circuits that control different aspects of this social behavior.

Does Chronic Hyperglycemia Affect Female Rat Sexual Behavior? Differences in Paced and Non-Paced Mating

IntroductionDiabetes mellitus has been associated with sexual dysfunction; however, in women this relationship is controversial. A study using a model of type 2 diabetes mellitus (DM2) failed to find a reduced receptivity in the non-paced mating (NPM), but the appetitive aspects of female sexual behavior have not been evaluated, for example, in the paced mating (PM) paradigm. AimTo evaluate all components of female sexual behavior (in NPM and PM) in a model of DM2 using ovariectomized (OVX) (treated with steroids) or intact female rats (non-OVX) in natural proestrus. MethodsNeonatal females (3–4 days) were administered streptozotocin (STZ, 70 mg/kg, intraperitoneally) or citrate buffer. At week 8, a glucose tolerance test was performed. At week 10, half of the females were OVX, and in the other half (non-OVX) the estrous cycle was monitored. At the twelfth week, the sexual behavior tests were conducted; OVX females were treated with estradiol benzoate (10 μg, −24 hours) and progesterone (3 mg, −4 hours), whereas the non-OVX were evaluated on vaginal proestrus. Main Outcome MeasuresWe registered in NPM and PM receptivity (lordosis quotient and intensity), as well as the number of proceptive and aggressive behaviors. Additionally, in PM we calculated the percentage of exits and the return latencies after receiving stimulation and the time the female remained in the male's compartment. ResultsThe STZ-treated females presented glucose intolerance and were hyperglycemic. Neonatal STZ treatment provoked changes in the females' sexual behavior depending on the paradigm and the hormonal condition. In the NPM, STZ-OVX females had decreased lordosis quotient and intensity and increased aggression, whereas, in the STZ-non-OVX females, there was a decrease in proceptivity; such changes were not observed in PM. Regardless of whether the STZ-treated females were OVX, they failed to perform the pacing behavior. Clinical ImplicationThese data support the idea that chronic mild hyperglycemia, like that observed in DM2 (which represents 90% of the clinical cases), provokes marginal changes in most aspects of female sexual behavior. Strengths & LimitationsThe main strength of this work is the evaluation of consummatory and motivational aspects of female sexual behavior in a model of DM2. The main limitation is the duration of the experimental design that does not resemble the course of the disease in humans. No histologic or biochemical analyses were performed. ConclusionThese results suggest that chronic hyperglycemia produces decreases in sexual behavior.Hernández-Munive AK, Rebolledo-Solleiro D, Fernández-Guasti A. Does Chronic Hyperglycemia Affect Female Rat Sexual Behavior? Differences in Paced and Non-Paced Mating. J Sex Med 2019;16:1130–1142.

Neurons expressing estrogen receptor α differentially innervate the periaqueductal gray matter of female rats

The periaqueductal gray matter (PAG) is a brainstem site involved in distinct autonomic and behavioral responses. Among them, the motor control of female sexual behavior, including lordosis, is well described. Lordosis reflex is highly dependent on increasing levels of estradiol that occur in the afternoon of the proestrus day in normally cycling females. This effect is thought to be mediated primarily via actions in the ventromedial nucleus of the hypothalamus (VMH). By binding to estrogen receptor α (ERα), estradiol changes the activity of VMH neurons that project to the PAG. Evidence also exists for the coordination of PAG outputs by estradiol-responsive neurons outside the VMH. However, a comprehensive analysis of these circuitries is not available. Using stereotaxic injection of the retrograde tracer Fluorogold in distinct columns of the PAG we performed a systematic mapping of neurons innervating the PAG and those coexpressing ERα immunoreactivity. We found that the forebrain projections to PAG columns are largely segregated and that most of the ERα expressing neurons preferentially target the lateral and the ventrolateral columns. Dual labeled neurons were mostly found in the intermediate subdivision of the lateral septal nucleus, the posterior aspect of the medial bed nucleus of the stria terminalis, the medial preoptic nucleus, the striohypothalamic nucleus and the ventrolateral VMH. Few dual labeled neurons were also observed in the arcuate nucleus, in the posterodorsal subdivision of the medial nucleus of the amygdala and in the ventral premammillary nucleus. Our findings indicate that ERα modulates sexual behavior in female rats via an integrated neural network that differentially innervate the columns of the PAG.

Prenatal undernutrition suppresses sexual behavior in female rats

Infectious, psychological and metabolic stresses in the prenatal and early neonatal period induce long-lasting effects in physiological function and increase the risk of metabolic disorders later in life. We examined the sexual behavior of female rats that were subjected to undernutrition in the prenatal period. Eight pregnant rats were divided into two groups: a maternal normal nutrition group (mNN; n = 4) and a maternal undernutrition group (mUN; n = 4), which received 50% of the daily food intake amount of the mNN group from gestation day 13 to delivery. Nine and seven female offspring were randomly selected from the mNN and mUN groups, respectively. Vaginal opening (VO), estrous cycle length, sexual behavior and mRNA expression levels of the factors that regulate sexual behavior were observed. In the mUN group, VO day was later, the estrous cycle was longer, and the lordosis quotient and lordosis rating were lower than in the mNN group; such differences were not seen in other sexual performances, such as ear wiggles, darts, kick bouts and box. The hypothalamic mRNA expression level of progesterone receptor (PR) A + B and oxytocin (OT) were significantly lower in the mUN group than in the mNN group. These findings indicated that prenatal undernutrition disrupted puberty onset, the estrous cycle, sexual behavior and hypothalamic mRNA expression of PR and OT in female rat pups.

Neuronal activity in the sagittalis nucleus of the hypothalamus after ovarian steroid hormone manipulation and sexual behavior in female rat

During extended observation of estrogen receptor (ER) α-immunoreactive neurons in the hypothalamus, we previously identified a novel nucleus, the Sagittalis Nucleus of the Hypothalamus (SGN), in the interstitial area between the arcuate nucleus and the ventromedial hypothalamic nucleus. The SGN exhibits sexual dimorphism in its volume and cell count, and estrous cycle related variations in ERα-immunoreactivity. These characteristics of the SGN implicate the nucleus in sex-biased brain functions and behaviors. In this study, we examined involvement of the SGN in sexual arousal in female rats. Immunohistochemical staining of c-Fos, a marker of neuronal activity was performed after administration of an estrus-inducing dose of estrogen and progesterone in ovariectomized female rats. Analysis of microscopic images showed a significant increase in the number of c-Fos-expressing neurons in the SGN following hormonal manipulation. Moreover, neuronal activity in the region exhibited a further increase after each animal was coupled with a male and allowed to mate. These results suggest that the SGN plays an important role in sexual activity in female rat.

Facilitation of sexual behavior in ovariectomized rats by estradiol and testosterone: A preclinical model of androgen effects on female sexual desire

In the United States and Canada, there are no approved treatments for hypoactive sexual desire disorder in postmenopausal women. Testosterone improves female sexual desire in naturally- and surgically-menopausal women maintained on estrogen replacement therapy, and long-term safety data from randomized placebo-controlled clinical trials has yielded promising results. However, the mechanisms associated with its efficacy are not known, and could be addressed using preclinical rodent models; yet there is no systematic evaluation of the effects of estradiol and testosterone on female rat sexual behavior. The aim of these studies was to assess whether testosterone propionate (TP) facilitates sexual behaviors, particularly appetitive sexual behaviors, in Long-Evans and Wistar ovariectomized (OVX) rats primed with estradiol benzoate (EB). In Experiment 1, Long-Evans OVX rats were treated with Oil (O), 10μg EB+O, O+200μg TP, 10μg EB+500μg progesterone (P), or 10μg EB+200μg TP. In Experiment 2a, Wistar OVX rats were treated with varying doses of EB (2.5, 5, or 10μg) 48h prior, and TP (0, 200, or 400μg) 4h prior to testing in a Latin-Square design. A subset of animals was used in Experiment 2b and treated sequentially with EB (0, 2.5, 5, or 10μg) followed by TP (0, 200, or 400μg, in a Latin-Square design) 48h prior to sexual behavior testing. All tests occurred in the bilevel pacing chamber. Frequencies of female appetitive (hops/darts, solicitations, level changes) and consummatory (lordosis quotient and magnitude) sexual behaviors as well as the number of defensive behaviors towards males were scored. Number of mounts, intromissions and ejaculations from males were also scored. In EB-primed OVX Long-Evans rats, 200μg TP administered 4h prior to testing facilitated hops/darts and lordosis ratings beyond EB alone, and to levels equivalent to EB+P. In contrast, that regimen was not successful in EB-primed OVX Wistar rats. When EB and TP were co-administered 48h prior to testing, 10μg EB+200μg TP significantly increased hops/darts and level changes beyond that observed by 10μg EB alone. In summary, the administration of EB and TP to OVX Long-Evans and Wistar rats facilitates appetitive measures of sexual behavior. Strain differences exist that likely reflect underlying differences in sensitivities to EB, and the EB-primed OVX Long-Evans rat may be useful for studying mechanisms of TP-facilitation of desire due to higher baseline sexual inhibition.

Editorial: Reproductive Neuroendocrinology and Social Behavior

Reproduction consists of various physiological events including fertilization, development of sexual characteristics, social behavior, maturation, and aging. Reproductive functions are ultimately regulated by the hypothalamus-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH) is a pivotal hypothalamic neuropeptide that regulates vertebrate reproduction (Schally et al., 1972). In tetrapods, GnRH neurons are located in the preoptic-hypothalamic region and project their fibers to the median eminence to regulate gonadotropin secretion from the anterior pituitary gland, which stimulates sex steroid secretion and gametogenesis in the gonads. It was also shown that central administration of GnRH can stimulate female sexual behavior in rats (Moss and McCann, 1973; Pfaff, 1973). GnRH release is regulated by other neuropeptides, neurotransmitters, and steroid hormones. Watanabe et al. summarize the role of gamma-amino butyric acid (GABA) in the regulation of GnRH neuronal activity and discuss functional consequences of GABAergic inputs to GnRH neurons in physiological aspects of reproduction. Recently, two neuropeptides containing the C-terminal Arg-Phe-NH2 (RFamide peptides), kisspeptin, and gonadotropin-inhibitory hormone (GnIH), emerged as critical accelerator, and suppressor, respectively, of vertebrate reproduction. Parhar et al. highlight classical and recent findings regarding the role of GnRH, kisspeptin, and GnIH in the regulation of social behaviors in fish, birds, and mammals, and discuss their importance in future biological and biomedical researches (Perspectives).