Diabetes mellitus and female sexual response: what do animal models tell us?

BACKGROUND: One of the less explored effects of diabetes mellitus (DM) is female sexual dysfunction. Females of different species have been used as models. AIM: To analyze the information of animal models of DM and female sexual response (FSR). METHODS: The literature of FSR in models of DM was reviewed. OUTCOMES: Paradigm- and diabetes-dependent changes have been found in various aspects of the FSR. RESULTS: Females in a type 1 DM (DM1) model show a decrease in the number of proestrus events, and ovariectomized females treated with sex hormones have been used. In these females, a reduction in lordosis has been reported; in proceptivity, the data are contradictory. These females present a decrease in sexual motivation that was restored after exogenous insulin. In the type 2 DM (DM2) model, females show regular estrous cycles, normal levels of lordosis behavior, and, depending on the paradigm, decreased proceptivity. These females display normal preference for sexually active males or their olfactory cues when having free physical contact; they lose this preference when tested in paradigms where physical interaction is precluded. CLINICAL TRANSLATION: Preclinical data showing the high deleterious effects of a DM1 model and the less drastic effects under a DM2 model are in accordance with clinical data revealing a much higher prevalence of sexual dysfunction in women with DM1 than DM2. STRENGTHS AND LIMITATIONS: The main strength is the analysis of the changes in various components of FSR in 2 models of DM. The main limitation is the difficulty in extrapolating the data on FSR from rats to women and that most studies focus on evaluating the impact of severe or chronic-moderate hyperglycemia/hyperinsulinemia on the sexual response, without considering other pathophysiologic alterations generated by DM. CONCLUSION: Females with severe hyperglycemia have a decrease in FSR, while those with moderate hyperglycemia show much less drastic effects.

Chronic moderate hyperglycemia does not alter sexual motivation in the female rat.

The relationship between diabetes mellitus type 2 (DM2) and sexual desire in women has not been systematically studied, therefore, animal models have been used for this purpose. When streptozotocin (STZ) is administered in the neonatal stage, the rat shows moderate chronic hyperglycemia and glucose intolerance in adulthood, resembling a DM2 model. These females show less alterations of sexual behavior (a slight decreased proceptivity and loss of paced mating) than their counterpart with severe hyperglycemia. However, the motivational components of copulation in female rats in this DM2 model have not been examined. The aim of this study was to evaluate female sexual motivation in a model of DM2 in three behavioral paradigms: the partner preference (PP), the sexual incentive motivation (SIM) and the odor preference test (OPT) tests. Neonatal females (3-4 days) were administered with streptozotocin (STZ, 70 mg/kg, intraperitoneally) or citrate buffer. At week 8, a glucose tolerance test was performed, females with blood glucose levels ≥ 250 mg/dl 60 min after a sucrose load (2 g/kg) were considered for the study. Behavioral tests were conducted at week 12, when the females were in natural proestrus. For PP we registered the time in each compartment and the sexual behavior, while in the SIM test, we calculated the time the females remained in each incentive zone. In these tests a castrated male and a sexually experienced male were used as stimuli. In OPT we evaluated the time the females spent sniffing the sawdust coming from cages housing these stimuli. In the PP and OPT hyperglycemic females behave similarly than controls, i.e., they retain a preference for sexually active males. In the SIM test there was a decrease in the time the hyperglycemic females remain in the vicinity of the sexually expert male. Data are discussed on the bases of the accessibility of the females to the stimuli.

Estradiol modulates the role of the spinal α6-subunit containing GABAA receptors in female rats with neuropathic pain.

The purpose of this study was to investigate the mechanisms underlying sex differences in the role of spinal α6-subunit containing GABAA (α6GABAA) receptors in rats with neuropathic pain. Intrathecal 2,5-dihydro-7-methoxy-2-(4-methoxyphenyl)-3H-pyrazolo [4,3-c] quinoline-3-one (PZ-II-029, positive allosteric modulator of α6GABAA receptors) reduced tactile allodynia in female but not in male rats with neuropathic pain. PZ-II-029 was also more effective in females than males in inflammatory and nociplastic pain. Ovariectomy abated the antiallodynic effect of PZ-II-029 in neuropathic rats, whereas 17ß-estradiol or 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT), estradiol receptor-α agonist, restored the effect of PZ-II-029 in ovariectomized rats. Blockade of estradiol receptor-α, using MPP (1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride), prevented the effect of 17ß-estradiol on PZ-II-029-induced antiallodynia in ovariectomized neuropathic females. Nerve injury reduced α6GABAA receptor protein expression at the dorsal root ganglia (DRG) and spinal cord of intact and ovariectomized female rats. In this last group, reconstitution with 17ß-estradiol fully restored its expression in DRG and spinal cord. In male rats, nerve injury reduced α6GABAA receptor protein expression only at the spinal cord. Nerve injury enhanced estradiol receptor-α protein expression at the DRG in intact non-ovariectomized rats. However, ovariectomy decreased estradiol receptor-α protein expression at the DRG. In the spinal cord there were no changes in estradiol receptor-α protein expression. 17ß-estradiol restored estradiol receptor-α protein expression at the DRG and increased it at the spinal cord of neuropathic rats. These data suggest that 17ß-estradiol modulates the expression and function of the α6GABAA receptor through its interaction with estradiol receptor-α in female rats.

Multiparity favors same-sex partner preference in male rats.

Same-sex partner preference is present in many mammals, including rodents. Several possible causal factors have been proposed for the establishment of this preference. The Fraternal Birth Order effect refers to the observation that older brothers increase the probability of homosexuality in men, but no experiment has analyzed this possibility. In this study, partner preference (tested in a three compartments box) and female and male sexual behavior (studied in a cylindrical arena) were evaluated in young male rats (3 months) born to multiparous mothers that had 4-6 previous gestations and around 12 months of age. Control groups were young male rats born to primiparous young (4 months) or aged (12 months) mothers. In the partner preference test, the males born to multiparous dams spent less time interacting with the receptive female and more time interacting with the sexually active male, and a 39% exhibited same-sex partner preference. This high percentage seems related to multiparity of their mothers and not to maternal age, because the males born to primiparous aged females (12 months) showed a similar low proportion of same-sex partner preference than the males born to young (4 months) primiparous females (4%). In the sexual behavior tests, no male born of a multiparous dam and with same-sex preference ejaculated and 54% displayed proceptivity and lordosis. Present results suggest that the fraternal birth order effect may occur also in rats.

Distribution of estrogen receptors alpha and beta in the brain of male rats with same-sex preference.

Two distinct estrogen receptors (ERs) exist, ERα and ERß. Both receptors participate in sexual differentiation of the rat brain and likely participate in the regulation of adult sexual orientation (i.e. partner preference). This last idea was investigated herein by examining males treated with the aromatase inhibitor, letrozole, administered prenatally (0.56 µg/kg G10-22). This treatment usually provokes same-sex preference in 1-2 males per litter. Vehicle-treated males (with female preference) and females in spontaneous proestrus (with male preference) were included as controls. ERα and ERß expression was analyzed by immunohistochemistry in brain areas known to control masculine sexual behavior and partner preference, like the medial preoptic area (MPOA), bed nucleus of the stria terminalis (BNST), medial amygdala (MeA) and ventromedial hypothalamic nucleus (VMH), as well as other brain regions suspected to participate in these processes. In addition, serum levels of estradiol were determined in all male groups. Letrozole-treated male rats that preferred sexually experienced males (LPM) showed over-expressed ERα in the hippocampal cornu Ammonis (CA 1, 3, 4) and dentate gyrus. The LPM group showed up-regulated ERß expression in the CA2 and reticular thalamic nucleus. The levels of estradiol did not differ between the groups. Higher expression of ERs in these males was different than their expression in females, with male sex-preference. This suggests that males with same-sex preference showed a unique brain, this sui generis steroid receptor expression probably participates in the biological underpinnings of sexual preference.

Spinal alarmin HMGB1 and the activation of TLR4 lead to chronic stress-induced nociceptive hypersensitivity in rodents.

Chronic stress affects millions of people around the world, and it can trigger different behavioral disorders like nociceptive hypersensitivity and anxiety, among others. However, the mechanisms underlaying these chronic stress-induced behavioral disorders have not been yet elucidated. This study was designed to understand the role of high-mobility group box-1 (HMGB1) and toll-like receptor 4 (TLR4) in chronic stress-induced nociceptive hypersensitivity. Chronic restraint stress induced bilateral tactile allodynia, anxiety-like behaviors, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) and activation of spinal microglia. Moreover, chronic stress enhanced HMGB1 and TLR4 protein expression at the dorsal root ganglion, but not at the spinal cord. Intrathecal injection of HMGB1 or TLR4 antagonists reduced tactile allodynia and anxiety-like behaviors induced by chronic stress. Additionally, deletion of TLR4 diminished the establishment of chronic stress-induced tactile allodynia in male and female mice. Lastly, the antiallodynic effect of HMGB1 and TLR4 antagonists were similar in stressed male and female rats and mice. Our results suggest that chronic restraint stress induces nociceptive hypersensitivity, anxiety-like behaviors, and up-regulation of spinal HMGB1 and TLR4 expression. Blockade of HMGB1 and TLR4 reverses chronic restraint stress-induced nociceptive hypersensitivity and anxiety-like behaviors and restores altered HMGB1 and TLR4 expression. The antiallodynic effects of HMGB1 and TLR4 blockers in this model are sex independent. TLR4 could be a potential pharmacological target for the treatment of the nociceptive hypersensitivity associated with widespread chronic pain.

Androgen receptors immunoreactivity in the rat brain of males with same-sex preference.

Androgen receptors (AR) are crucial in the control of male sexual behavior and sex preference. AR are particularly concentrated in areas related with the neuroendocrine control of sex preference including the medial amygdala (MeA), the ventromedial nucleus of the hypothalamus (VMH), the bed nucleus of the stria terminalis (BNST), the medial preoptic area (MPOA), the nucleus accumbens (Acb), the suprachiasmatic (SCh) and supraoptic (SO) nuclei, but also seem to be important for the control of reproductive processes in the hippocampus (CA1-CA4 and dentate gyrus, DG). In the present study we analyzed the density of AR in these brain areas of adult male rats with sexual preference (established in a three-compartment box). Same-sex preference was produced in male rats by the prenatal administration of the aromatase inhibitor, letrozole (0.56 µg/kg/ml s.c. G10-22) that usually produces 1-2 animals per litter with same sex preference, while the others retain a female sex preference. We also included a group of proestrus females that had a clear preference for a sexually active male. AR were analyzed by immunocytochemistry using PG21 as primary antibody. We also measured total plasma testosterone concentrations by radioimmunoassay. In males with same sex preference there was a specific AR overexpression in CA3 and CA4 that suggests a feminized pattern because females in proestrus trend to show a higher density of AR in these hippocampal areas. Sex differences in AR density were found in the anterior cingulate cortex (ACg) and frontoparietal cortex (FrPa). Serum levels of testosterone did not differ between groups. Data are discussed based on the role of AR in the hippocampus.

Pharmacological Interaction of Quercetin Derivatives of Tilia americana and Clinical Drugs in Experimental Fibromyalgia.

Fibromyalgia (FM) is a pain syndrome characterized by chronic widespread pain and CNS comorbidities. Tilia americana var. mexicana is a medicinal species used to treat anxiety, insomnia, and acute or chronic pain. However, its spectrum of analgesic efficacy for dysfunctional pain is unknown. To investigate a possible therapeutic alternative for FM-type pain, an aqueous Tilia extract (TE) and its flavonoid fraction (FF) containing rutin and isoquercitrin were evaluated alone and/or combined with clinical drugs (tramadol-TRA and pramipexol-PRA) using the reserpine-induced FM model in rats. Chromatographic analysis allowed the characterization of flavonoids, while a histological analysis confirmed their presence in the brain. TE (10-100 mg/kg, i.p.) and FF (10-300 mg/kg, i.p.) produced significant and dose-dependent antihyperalgesic and antiallodynic effects equivalent to TRA (3-10 mg/kg, i.p.) or PRA (0.01-1 mg/kg, s.c.). Nevertheless, the combination of FF + TRA or FF + PRA resulted in an antagonistic interaction by possible competitive action on the serotonin transporter or µ-opioid and D2 receptors, respectively, according to the in silico analysis. Flavonoids were identified in cerebral regions because of their self-epifluorescence. In conclusion, Tilia possesses potential properties to relieve FM-type pain. However, the consumption of this plant or flavonoids such as quercetin derivatives in combination with analgesic drugs might reduce their individual benefits.

Retracted: Sexual orientation, neuropsychiatric disorders and the neurotransmitters involved.

According to the neuro-hormonal theory, sexual orientation in humans develops in the womb under the influence of sex hormones. In this article, we review the evidence from basic research on the possible role of neurotransmitters on influencing sexual orientation. We show that pharmacological or genetically induced changes in neurotransmitter systems during development might, by hormone-mediated structural and functional brain changes, result in alterations in sexual preference in animal models. We propose that in humans this mechanism may contribute to the relationship between non-heterosexual orientation and increased prevalence of neuropsychiatric disorders. Data to support this idea are reviewed. We suggest that altered neurotransmitter levels during development will increase the chance for both non-heterosexual differentiation of the brain and neuropsychiatric disorders. This possibility may have clinical implications, because medication given to a pregnant woman may, in this way, alter brain development of the fetus in a permanent way.

Lack of interaction between prenatal stress and prenatal letrozole to induce same-sex preference in male rats.

Same-sex partner preference between males has been observed in all species in which this behavior has been studied. Disruption of brain estradiol synthesis during development has been proposed as one of the biological causes underlying this behavior in some mammals. In support of this possibility, perinatal administration of aromatase inhibitors (such as letrozole) to male rat pups, induces around half of them to have same-sex preference and female sexual behavior in adulthood. Another putative factor that modifies sex preference is prenatal stress. Several stress protocols, applied to the pregnant dam, cause some of the adult male progeny to have an increased male preference, a decreased preference for the female, and lordosis behavior. Interestingly, these effects of stress might be mediated by its inhibitory action on brain aromatase. The aim of the present study was to analyze a possible interaction between these two factors in male rats. Pregnant dams were exposed to one of the four treatments across gestation days 10-22 (G10-G22): 1) vehicle-treated non-stressed controls; 2) letrozole (0.56 µg/kg); 3) 30 min immobilization stress); 4) both letrozole and stress combined. The male offspring were tested in adulthood for partner preference in a three-chambered arena, where we also recorded the masculine and feminine sexual behaviors. One week later males were tested for masculine and feminine sexual behavior in cylindrical arenas where they interacted for 30 min with a receptive female and thereafter with a sexually active male for another 30 min. Letrozole, stress and their combination resulted in same-sex preference in 40, 31 and 50% of males, respectively, compared to 5% in the control group. In the sexual behavior tests, prenatal stress reduced the percentage of males displaying intromissions and ejaculation (impaired masculinization), while letrozole mainly increased lordosis (impaired defeminization). The males prenatally submitted to stress and treated with letrozole presented these behavioral features but did not differ from both treatments given independently. The results indicate that the changes induced by stress or the aromatase inhibition produced by letrozole only accounts for a shift in partner preference in around half of the males and that there was no interaction between these two factors.

Does the antidepressant-like effect of mirtazapine and venlafaxine differ between male and female rats? / ¿El efecto de tipo antidepresivo de la mirtazapina y la venlafaxina difiere entre ratas macho y hembra?

Abstract Introduction Depression is a global health problem with nearly 350 million people affected, mainly women. However, nowadays a rising amount of men are being diagnosed. This makes necessary the screening of new treatment options that are effective in women as well as in men. Objective To analyze if the administration of mirtazapine and venlafaxine to male and female rats shows a sex-related antidepressant-like effect, and the possible associated neurochemical mechanisms. Method Mirtazapine (40 mg/kg) or venlafaxine (60 mg/kg) were administered subchronically to young adult male and female (ovariectomized and steroid-primed) rats, and their antidepressant-like effects were evaluated using the forced swim test (FST). The active behaviors, swimming and climbing, were also analyzed. Results a) mirtazapine and venlafaxine reduced immobility in the FST in males and females; b) both antidepressants increased climbing and swimming in male rats; c) in female rats, mirtazapine and venlafaxine only increased swimming. Discussion and conclusion In males, the effects of mirtazapine and venlafaxine seem to be produced by the activation of the serotonergic and noradrenergic systems. Conversely, estradiol might be modulating the mechanisms of action of both antidepressants in females producing only an increased swimming and suggesting the participation of the serotonergic system.

Resumen Introducción La depresión es un trastorno psiquiátrico que representa un problema de salud mundial. Afecta a cerca de 350 millones de personas, predominantemente mujeres. Sin embargo, algunos reportes indican que su incidencia en hombres está aumentando, por lo que es necesario buscar opciones de tratamiento que sean igualmente efectivas en ambos sexos. Objetivo Analizar si existen diferencias relacionadas con el sexo en el efecto de tipo antidepresivo de la mirtazapina y la venlafaxina, y considerar los posibles mecanismos neuroquímicos involucrados. Método se administraron mirtazapina (40 mg/kg) o venlafaxina (60 mg/kg) en esquema subcrónico a grupos independientes de ratas macho y hembra ovariectomizadas tratadas con estradiol y progesterona. Se evaluaron el efecto tipo antidepresivo y las conductas activas (nado y escalamiento) utilizando la prueba de nado forzado (PNF). Resultados a) tanto la mirtazapina como la venlafaxina redujeron la inmovilidad en la PNF en machos y hembras; b) ambos antidepresivos incrementaron las conductas activas en machos; c) en hembras, la mirtazapina y la venlafaxina produjeron un aumento del nado, pero no modificaron el escalamiento. Discusión y conclusión En machos, los efectos de la mirtazapina y la venlafaxina en la PNF se deben a su acción sobre los sistemas serotonérgico y noradrenérgico; en cambio, en hembras sólo se modifica la conducta de nado, lo que sugiere que el estradiol modula las acciones de ambos antidepresivos sobre el sistema serotoninérgico.

Diabetic female rats exhibit defensive aggression during mating / Las ratas hembra diabéticas exhiben agresión defensiva durante la cópula

Abstract Introduction Few reports have analyzed the putative association between diabetes mellitus type 1 (DM1) and aggressiveness. A previous study using a model of DM1 reported an increase in aggressive behaviors (AB) of females against the male during mating, which was prevented by insulin. However, it was unclear if such aggression was defensive or offensive. Objective To evaluate the different components of aggressiveness of hyperglycemic female rats in two distinct mating paradigms. Method DM1 was modeled in OVX Wistar rats by injecting streptozotocin (STZ) diluted in citrate buffer (50 mg/kg, i.p., for 2 consecutive days). Ten days later, female rats were treated with estradiol benzoate (10 microg, -24 hours) and progesterone (3 mg, -4 hours). A group of STZ-treated animals was administered with a long-acting insulin analogue (glargine) every 12 hours for 8 days. Aggression was recorded in non-paced mating (NPM) and paced mating (PM) paradigms. We registered: the first attack latency (FAL), the proportion of females that presented AB and its type (boxing, bites, lateral kicks and twist) and if AB were exhibited defensively or offensively. Results Hyperglycemic rats showed an increase in lateral kicks in NPM, whereas in PM they exhibited an increase in bites. These behaviors were always defensive and there were no changes in FAL. Insulin reduced AB. Discussion and conclusion Data indicate that the aggressiveness of hyperglycemic female rats is a form of defense against the proximity of the male and add information about the role of insulin on their modulation.

Resumen Introducción Pocos trabajos han evaluado la relación entre diabetes mellitus tipo 1 (DM1) y la agresividad. En un estudio se reportó un aumento en las conductas agresivas (CA) de las hembras contra el macho durante la cópula, las cuales se reducen administrando insulina. No está claro si estas CA se expresan de manera defensiva u ofensiva. Objetivo Evaluar diferentes componentes de la agresividad de ratas hembras hiperglucémicas en dos paradigmas de cópula. Método La DM1 fue modelada en ratas Wistar ovariectomizadas inyectando estreptozotocina (STZ) disuelta en buffer de citratos (50 mg/kg, i.p., durante dos días consecutivos). Diez días después, se les administró benzoato de estradiol (10 microg, -24 horas) y progesterona (3 mg, -4 horas). A un grupo tratado con STZ se le administró un análogo de insulina (glargina) cada 12 horas durante ocho días. La agresión se registró en los paradigmas de cópula no regulada (NPM) y regulada (PM). Se registraron: la latencia al primer ataque (LPA), la proporción de hembras que exhibieron alguna CA, el tipo (boxeo, mordidas, patadas laterales y giros) y si se presentaron de manera defensiva u ofensiva. Resultados Las hembras diabéticas mostraron un aumento en las patadas laterales en NPM mientras que en PM exhibieron más mordidas. Las conductas fueron defensivas, no hubo cambios en la LPA. La insulina redujo la expresión de CA. Discusión y conclusión Los datos indican que las CA de las hembras hiperglucémicas son una forma de defensa contra la proximidad del macho y agregan información sobre el papel de la insulina en su modulación.

Observing Erotic Videos With Heterosexual Content Induces Different Cerebral Responses in Homosexual and Heterosexual Men.

To determine the cerebral functionality associated with the perception and processing of erotic stimuli in men with different sexual orientation, this work evaluated the electroencephalographic activity (EEG) from several cortical areas, as well as subjective arousal in homosexual and heterosexual men during observation of an erotic film with heterosexual content. The heterosexual men rated the erotic video with higher general and sexual arousal than the homosexual participants. During observation of the neutral and erotic videos, both groups showed a decreased amplitude of the alpha band in prefrontal and parietal cortices, indicating increased attention. When watching the erotic video, the homosexual men showed an increased amplitude of the theta and fast bands only in the prefrontal cortex, which could be related to the cognitive processing of the erotic stimulus. These EEG results should broaden our knowledge of the cortical mechanisms related to the different perception and processing of erotic stimuli in men with different sexual orientations.

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

INTRODUCTION: Depression 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. AIM: To 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. METHODS: Mirtazapine (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. RESULTS: Mirtazapine (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. CONCLUSIONS: Mirtazapine 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.

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

INTRODUCTION: Diabetes 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. AIM: To 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. METHODS: Neonatal 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 MEASURES: We 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. RESULTS: The 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 IMPLICATION: These 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 & LIMITATIONS: The 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. CONCLUSION: These 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.

Establishment of partner preference in male rats: Effect of prenatal letrozole and sexual experience.

Repeated testing for masculine sexual behavior influences female sex preference in males. Males perinatally treated with aromatase inhibitors show male preference, but also copulate with the receptive female. Such copulation modifies sex preference most likely because of its rewarding properties. In this study, we intended to equal the incentive value of both stimuli -in the sex preference test- by using receptive females with vaginal occlusion. Vehicle and letrozole-treated (0.56 µg/kg, gestation days 10-21) males were repeatedly tested for sex preference at 40, 55, 70, 85 and 100 days of age. These ages were selected because males of 40 days are unable to copulate, while by 100 days of age almost all males show the complete repertoire of masculine sexual behavior. At 40 days of age, males of all groups fail to show sex preference and none of them was able to copulate. In controls of 100 days of age all males showed female-sex preference and all intromitted the female. A large proportion (44%) of vehicle-treated males that could not copulate the female showed male preference. Twenty to 30% of the prenatally letrozole treated males also had same-sex preference even if they could copulate; and most of them (67%) had a male preference when copulation was precluded. These data support the idea that copulation is crucial for developing a female preference in control animals. The results suggest that brain changes produced by estrogens along early development and stimuli coming from the partner are essential for shaping sex preference.

Sleep architecture is altered in the reserpine-induced fibromyalgia model in ovariectomized rats.

Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome with various concomitant symptoms like sleep disorders. FM patients are mainly women and menopause might play an important role in the altered processing of somatosensory information. Adverse effects and moderated efficacy of drugs promote treatment discontinuation by patients. Animal models of FM report pain and depression-like behaviors, but none of them have explored sleep disturbance as possible marker in the preclinic diagnostic. The aim of this study was to investigate alterations of the sleep architecture in the reserpine (RES)-induced FM model in ovarectomized (OVX) rats. The behavioral thresholds of nociceptive response in the experimental FM were analyzed in a first block using muscle pressure, tactile response and allodynia to cold stimulus. In a second block, the sleep-wake cycle was examined in a polysomnographic study. Groups (n = 8) consisted in: (a) no treatment, (b) RES vehicle, (c) RES alone, (d) RES + vehicle of fluoxetine (FLX, antidepressant reference drug), and (e) RES + FLX. Our results demonstrated that RES induced pain-related behavior (50-70%) in OVX rats and altered sleep architecture by the increase of total wake time (38%), diminution of the no-REM stage (SWS-I 33% and SWS-II 76%), and abolition of the REM sleep, effects that were partially reverted in the presence of FLX. In conclusion, our results support the face validity of the RES-induced pain-related behavior as FM model showing nociceptive behavioral responses associated to sleep alterations observed as symptoms in FM patients; thus, these evidences substantiate its usefulness to look for alternatives of treatment for FM symptoms.

Influence of sex and estrous cycle on blood glucose levels, body weight gain, and depressive-like behavior in streptozotocin-induced diabetic rats.

Depression is the most common psychiatric disorder in diabetic patients, showing higher rates in women than in men. This comorbidity has been studied in rodents using the streptozotocin (STZ)-induced diabetes (DM) model, consistently reporting a depressive-like profile in males. Few articles have examined these disturbances in females (ovariectomized or combined with male rats) yielding controversial results. This work was aimed to study whether there are sex differences in the depressive-like profile of STZ-treated male and naturally cycling female Wistar rats. We also analyzed the possible influence of the estrous cycle in females. DM was induced by injecting STZ (50 mg/kg, i.p.) in 2 consecutive days. Ten days later, the depressive-like profile was assessed in the Forced-Swim Test (FST). Locomotion and motor coordination were also evaluated. Body weight and blood glucose levels were registered at the beginning and at the end of the experiment; the estrous cycle, food and water intake were daily monitored. All diabetic subjects showed increased blood glucose levels, polyphagia, polydipsia and decreased body weight as compared to controls, but males were more susceptible to STZ-treatment than females pooled in all phases of the estrous cycle. After treatment with STZ, males and females in proestrus/estrus (P/E) exhibited a depressive-like profile in the FST (increased immobility and reduced swimming); females in metestrus/diestrus were unaffected. The only sex difference observed was a more pronounced reduced swimming in STZ-treated P/E females compared with hyperglycemic males. No changes in locomotion or motor coordination were found. This work emphasizes estrous cycle differences in STZ-treated rats, and in the resultant depressive-like profile. It also supports clinical evidences made in women with DM and stresses the importance of studying STZ-treated naturally cycling females and their estrous cycle phases.

Male rats with same-sex preference show higher immobility in the forced swim test, but similar effects of fluoxetine and desipramine than males that prefer females.

Sex preference in male rats is partly determined by the organizational action of estradiol. Thus, several paradigms have used aromatase inhibitors to manipulate sex preference. We recently showed that a subpopulation of male rats prenatally treated with letrozole (0.56 µg/kg, G10-G22), a non-steroidal third generation aromatase inhibitor, had same-sex preference, female sexual behavior (including lordosis and proceptivity) and penile erections when exposed to other males. These males, in addition, displayed high levels of experimental anxiety in the plus maze test and were insensitive to the anxiogenic-like acute effect of FLX (10 mg/kg). The two main purposes of the present work were: a) to study the behavioral profile of males displaying same-sex preference in the forced swim test (FST), and b) to analyze if the antidepressant-like effect of the subchronic treatment with FLX (10 mg/kg, 3 times) or desipramine (DMI, 10 mg/kg, 3 times) vary according to sex preference. Males treated prenatally with letrozole with same-sex preference showed more immobility and less active behaviors (swimming and climbing) in the FST than males with female preference. Subchronic treatment with FLX and DMI reduced immobility when compared to saline controls, while FLX increased swimming and DMI increased climbing behavior. Treatments were equally effective in males with preference for other males and those that preferred females. These results indicate that an association exists between prenatal letrozole treatment, same-sex preference and immobility in the FST.

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.