Reduced sexual motivation of diabetic female rats: Restoration with insulin.

The aim of this study was to evaluate female rat sexual motivation in a model of diabetes mellitus type 1. Severe hyperglycemia was induced in ovariectomized Wistar rats by injecting streptozotocin [STZ, 100 mg/kg, i.p.]. Ten days later, females received estradiol benzoate (10 µg/rat, s.c.) plus progesterone (3 mg/rat, s.c.). A group of STZ-treated animals was administered with insulin (2-4 U) every 12 h for 10 days, which normalized glucose levels. In the partner preference (PP) and sexual incentive motivation (SIM) tests, control females spent more time close to a sexually experienced male (SE) than with a castrated male (CM). STZ-treated females stayed the same amount of time with both stimuli, that is, they lost their sexual preference. We also evaluated the sense of smell using two behavioral tests, one related to sexual odors (SO) and another one to food odors (FO). In the SO test, control females spent more time sniffing the sawdust coming from cages that contained SE males; hyperglycemic females remained the same amount of time sniffing the sawdust of both stimuli: SE and CM. In the FO test, no differences were found between control and STZ-treated groups. Insulin treatment reverted the changes observed in hyperglycemic females in the PP, SIM and SO tests. These data suggest that severe hyperglycemia decreases sexual motivation and that insulin recovers such diminution.

Neuropeptide and steroid hormone mediators of neuroendocrine regulation.

To maintain the health and well-being of all mammals, numerous aspects of physiology are controlled by neuroendocrine mechanisms. These mechanisms ultimately enable communication between neurones and glands throughout the body and are centrally mediated by neuropeptides and/or steroid hormones. A recent session at the International Workshop in Neuroendocrinology highlighted the essential roles of some of these neuropeptide and steroid hormone mediators in the neuroendocrine regulation of stress-, reproduction- and behaviour-related processes. Accordingly, the present review highlights topics presented in this session, including the role of the neuropeptides corticotrophin-releasing factor and gonadotrophin-releasing hormone in stress and reproductive physiology, respectively. Additionally, it details an important role for gonadal sex steroids in the development of behavioural sex preference.

Rutin antinociception involves opioidergic mechanism and descending modulation of ventrolateral periaqueductal grey matter in rats.

BACKGROUND: Rutin is a bioflavonoid found in fruits, vegetables and plants used in traditional medicine to alleviate pain. However, rutin's scientific evidence for the modulation of pain and its mechanism of action is lacking. It is well known that the periaqueductal grey matter (PAG) contains opioidergic neural circuits involved in the modulation of descending nociception. The aim of this study was to investigate if antinociceptive activity of rutin is modulated by the PAG circuitry involving participation of opioid receptors. METHODS: The experimental design included groups of rats receiving rutin systemically (30-1000 mg/kg) or microinjected into the vlPAG (8-32 nmol/4 µL) alone or in the presence of an opioid antagonist, naltrexone (5 mg/kg, i.p. or 26 nmol/4 µL, respectively). Nociception was assessed using the formalin test and compared versus the reference drugs, tramadol and morphine. RESULTS: Systemic or intra-vlPAG administration of rutin significantly decreased both phases of the formalin test. Antinociceptive responses of the reference drugs were prevented by naltrexone, whereas the antinociceptive effect of rutin was inhibited by this antagonist mainly in the phase II of the formalin test. CONCLUSIONS: Our results provide evidence that rutin produces antinociceptive effects involving central modulation of the vlPAG descending circuit partly mediated by an opioidergic mechanism.

Unraveling the modulatory actions of serotonin on male rat sexual responses.

Animal studies and clinical investigations reveal that serotonin plays a central role in the control of the ejaculatory threshold. The chronic use of selective serotonin reuptake inhibitors (SSRIs) frequently results in sexual dysfunction, inviting to analyze the modulatory actions of serotonin on male sexual function in depth. Even though the main effect of serotonin on male sexual responses is inhibitory, this neuromodulator also mediates brief important stimulatory actions. Serotonin (5-HT) can activate two intracellular signaling pathways: a lower-threshold facilitatory pathway, and a higher-threshold inhibitory pathway, leading to biphasic effects. We propose that these divergent actions are related to the stimulation or inhibition of glutamatergic and GABAergic interneurons. Experimental evidence suggests that low 5-HT concentrations produce stimulatory actions on male ejaculatory aspects that might be mediated by the blockade of the GABAergic neurotransmission in the MPOA and spinal cord, which in turn releases a tonic inhibition that allows other neurotransmitters such as glutamate, noradrenaline, oxytocin and dopamine to initiate a sequence of molecular events resulting in the expression of ejaculation. Similar serotonin actions, mediated via interneurons, have been proposed for the regulation of other processes and occur in many central nervous system areas, indicating that it is not an isolated phenomenon.

Copulation without seminal expulsion: the consequence of sexual satiation and the Coolidge effect.

The studies of sexual satiety in male rats under the Coolidge effect indicate that males reassume copulation until ejaculation. Recently, it was demonstrated that sexually satiated males preserve the motor patterns of intromission and ejaculation, also penile erection, but not seminal expulsion. The first aim was to investigate if penile erections displayed by sexually satiated males dislodge the seminal plugs from the vagina and its effect on sperm transcervical transport. The second aim was to determine the recovery time of seminal expulsion after sexual satiety and its optimal ability to induce pregnancy. Results show that during the Coolidge effect males were able to dislodge the seminal plugs deposited by others (experiment 1A) disturbing the sperm transport (experiment 1B) then interfering with pregnancy (experiment 1C). After satiation, the ejaculate parameters recover slowly: it starts after 10 days with the seminal plug formation, and continues with an increase in sperm count in the uterus 15 days post-satiety (experiment 2). Sexually satiated males impregnated only 28% of the females during 15 days of cohabitation, whereas, satiated males that rested for 15 days impregnated 89% of the females (experiment 3). We concluded that males with successive ejaculations remain potential rivals, because they may disrupt the sperm transport of other males. The ejaculate features recovery after sexual satiety is gradual, begins with the secretions of the sex accessory glands and is followed by the sperm count. Full fertility recovery is reached after 15 days of sexual abstinence when males are able to impregnate most females.

Influence of the brain sexual differentiation process on despair and antidepressant-like effect of fluoxetine in the rat forced swim test.

Sex differences exist in the depressive disorder prevalence and response to treatment. Several studies suggest that females respond better than males to the action of selective serotonin reuptake inhibitors (SSRIs), suggesting that gonadal hormones modulate mood and the response to these drugs. Sexual steroid hormones exert organizational actions (perennial and on early development) and activational effects (transient and on differentiated tissues). The aim of this study was to analyze sex differences in the forced swim test (FST) in animals without treatment and after fluoxetine (FLX, 0, 2.5, 5.0 and 10.0mg/kg). Initially, we compared male and female adult rats under control conditions or after altering their sexual differentiation process (at day 5 postnatally, PN, 60µg of testosterone propionate to females and male castration to induce or preclude masculinization, respectively). To further analyze if the sex differences depend on organizational or activational steroid hormone action we tested the same animals before and after adult gonadectomy. To prevent variations depending upon the estrous cycle, control and masculinized females were tested in estrus. Control females showed lower immobility and required lower doses of FLX (5mg/kg), to show an antidepressant-like effect, than males (10mg/kg), even after adult gonadectomy. In control males adult orchidectomy prevented FLX's action. Neonatally masculinized females exhibited analogous levels of immobility than control ones; before ovariectomy they responded to FLX similar to controls, but after the surgery they did not respond to fluoxetine. Neonatally orchidectomized males exhibited similar immobility values and response to FLX than control females. The findings suggest that the sex difference in despair depends on the hormones organizational effects and, in males, the response to FLX relies on organizational and activational actions.

Sex, stress, and mood disorders: at the intersection of adrenal and gonadal hormones.

The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design.

[2D:4D finger ratio and language development]. / Indice digital D2:D4 y desarrollo del lenguaje.

INTRODUCTION: A possible hormonal influence in language development has been suggested in the recent years. The 2D:4D finger ratio is an indirect measure for prenatal androgen exposure. It is negatively related to prenatal testosterone and positively related to prenatal estrogen, resulting in a lower ratio for men and a larger ratio for women. It can be explored in children as young as 2 years old. AIM: To study if an association exists between the 2D:4D finger ratio and language development (vocabulary) and/or language problems. SUBJECTS AND METHODS: The lengths of the second digit (index finger) (2D) and the fourth digit (ring finger) (4D) were measured in 97 preschoolers and the Language Development Survey was administered to the parents. RESULTS: A weak negative correlation between language development (vocabulary) and right 2D:4D ratio was found in both sexes for children aged 4 or less years, significant only in boys. A strong negative correlation between language articulation problems and right 2D:4D ratio in both sexes for children aged 3 or less years, and a lower negative correlation between articulation problems and right 2D:4D ratio were found for boys aged 4 or less years. CONCLUSION: Findings suggest an important role for testosterone in language development (vocabulary) and a possible influence on articulation problems, probably through higher testosterone levels.

Índice digital D2: D4 y desarrollo del lenguaje / 2D: 4D Finger ratio and landguage development

Introducción. En años recientes, se ha sugerido una posible influencia hormonal en el desarrollo del lenguaje. El índice digital D2:D4 es una medida indirecta de la exposición prenatal a andrógenos. Se relaciona negativamente con la testosterona prenatal y positivamente con el estrógeno prenatal, lo que determina un índice bajo en varones y alto en mujeres. Puede explorarse a partir de los dos años de vida. Objetivo. Estudiar si hay una asociación entre el índice digital D2:D4 y el desarrollo de lenguaje (vocabulario) y/o los problemas del lenguaje. Sujetos y métodos. Se midieron las longitudes del dedo índice (D2) y el dedo anular (D4) en 97 preescolares y sus padres contestaron el sondeo del desarrollo del lenguaje. Resultados. Se encontró una correlación débil negativa entre el desarrollo de lenguaje (vocabulario) y el índice digital derecho D2:D4 en niños de ambos sexos de 4 o menos años de edad, significativa sólo en los varones. Se halló una fuerte correlación negativa entre los problemas de articulación y el índice digital derecho D2:D4 para niños de ambos sexos de 3 o menos años, y una correlación negativa baja entre los problemas de articulación del lenguaje y el índice digital derecho D2:D4 para niños de 4 o menos años. Conclusión. Estos resultados sugieren que la testosterona influye en el desarrollo de lenguaje (vocabulario) y en los problemas de articulación, probablemente a través de dosis mayores (AU)

Introduction. A possible hormonal influence in language development has been suggested in the recent years. The 2D:4D finger ratio is an indirect measure for prenatal androgen exposure. It is negatively related to prenatal testosterone and positively related to prenatal estrogen, resulting in a lower ratio for men and a larger ratio for women. It can be explored in children as young as 2 years old. Aim. To study if an association exists between the 2D:4D finger ratio and language development (vocabulary) and/or language problems. Subjects and methods. The lengths of the second digit (index finger) (2D) and the fourth digit (ring finger) (4D) were measured in 97 preschoolers and the Language Development Survey was administered to the parents. Results. A weak negative correlation between language development (vocabulary) and right 2D:4D ratio was found in both sexes for children aged 4 or less years, significant only in boys. A strong negative correlation between language articulation problems and right 2D:4D ratio in both sexes for children aged 3 or less years, and a lower negative correlation between articulation problems and right 2D:4D ratio were found for boys aged 4 or less years. Conclusion. Findings suggest an important role for testosterone in language development (vocabulary) and a possible influence on articulation problems, probably through higher testosterone levels (AU)

Reduction in the latency of action of antidepressants by 17 beta-estradiol in the forced swimming test.

RATIONALE: Antidepressants (ADs) are slow to produce their therapeutic effect. This long latency promotes the development of new strategies to short their onset of action. Previous reports indicated that 17beta-estradiol (E(2)) promotes the antidepressant-like activity of fluoxetine (FLX) and desipramine (DMI) in the forced swimming test (FST). OBJECTIVE: The aim of the present work was to analyze if E(2) reduces the antidepressant-like onset of action of venlafaxine (VLX), FLX, and DMI. MATERIALS AND METHODS: Independent groups of ovariectomized female Wistar rats were tested in the FST and in the open field after chronic (1 to 14 days) treatment with VLX (20 mg/kg/day), FLX (1.25 mg/kg/day), or DMI (1.25 mg/kg/day) alone or in combination with a single injection of E(2) (2.5 microg/rat sc, 8 h before FST). RESULTS: VLX, FLX, or DMI by themselves at these doses did not induce changes in the FST at short intervals after their injection (from 1 to 7 days). The addition of E(2) promoted the antidepressant-like effect of VLX and DMI as early as day 1. Such action was also evident after 3, for FLX, and 14 days for both FLX and DMI, but not for VLX. The behavioral actions of these ADs combined with E(2) were not accompanied by increases in general activity in the open-field test. CONCLUSION: E(2) clearly reduced the latency to the onset of action for these ADs in the FST. These results represent an interesting therapeutic strategy for the treatment of depression in perimenopausal women.

Aging increases the susceptibility to develop anhedonia in male rats.

The objective of this study was to establish the effect of aging on the development of anhedonia, a core feature of depression. Young and old male Wistar rats (of around 3-5 and 12-15 months, respectively) were exposed to a chronic variable stress (CVS) schedule for 3 weeks. CVS produced anhedonia, indicated by a reduction in the intake of a sucrose solution (1%), in 8 out of 23 (35%) young rats and in 19 out of 26 (73%) old rats, implying that old animals are more susceptible to stress and develop anhedonia more readily than young animals. Young and old anhedonic rats showed a similar temporal course in the reduction of sucrose consumption, reaching the anhedonic state after 2 weeks of CVS exposure. Compared with young animals, old rats had lower basal serum testosterone and estradiol levels. The systemic levels of corticosterone did not vary between both age groups. No significant pathological condition was detected in old animals. It is suggested that the higher susceptibility to develop anhedonia in male rats could be associated to neuroendocrine changes consequent to aging.

Maternal condition reduces fear behaviors but not the endocrine response to an emotional threat in virgin female rats.

Lactating dams and maternal virgin females are less fearful in behavioral tests compared with non-maternal animals, suggesting that maternal condition per se reduces the negative value of threatening stimuli. In addition, lactating females exhibit a diminished hypothalamic-pituitary-adrenal response to potential environmental threats. Can the maternal condition, independently of the endocrine profile of lactation, promote a reduction in the behavioral as well as in the endocrine response to an emotional stressor? To answer this question, anxiety-related and fear behaviors as well as the levels of corticosterone were evaluated in response to a bright-lit open field-loud noise model in maternal and non-maternal non-ovariectomized virgin females and lactating dams in the presence of the pups. Maternal animals, both lactating and virgin, presented an increased exploration of the bright-lit open field and a significant reduction of fear behaviors, indicated by the decreased flight and immobility responses to the subsequent activation of a loud noise, in comparison to non-maternal virgins. Interestingly, maternal virgin females, as non-maternal rats, showed high corticosterone plasma levels, in contrast to the lower endocrine response exhibited by lactating dams when confronted to this threat. Present results suggest that maternal condition allows females to take risks when caring for their young, a behavioral strategy that is independent of the reduced hypothalamic-pituitary-adrenal axis response characteristic of lactation. This evidence points towards a clear dissociation in the mechanisms regulating behavioral and endocrine responses to emotional stressors during motherhood.

c-Fos expression related to sexual satiety in the male rat forebrain.

The long term inhibition of masculine sexual behavior after repeated ejaculations is known as sexual satiety. To investigate the brain areas that may regulate sexual satiety, c-Fos expression was studied in different groups of sexually experienced male rats: controls not allowed to copulate, males allowed two or four ejaculations and animals allowed to reach sexual satiety. Interestingly, males that ejaculated two or four times had similar c-Fos densities in all the evaluated brain regions, except for the suprachiasmatic nucleus. Similarly, sexually satiated males had analogous c-Fos densities in all the evaluated brain areas independently of the number of ejaculations required to reach satiety. Sexual activity (evidenced in males that ejaculated two or four times) increased c-Fos levels in the anteromedial bed nucleus of the stria terminalis, claustrum, entorhinal cortex, medial preoptic area, nucleus accumbens core, suprachiasmatic nucleus and supraoptic nucleus; however, sexual satiety did not modify c-Fos expression in these regions. Sexually satiated males had increased c-Fos densities in the ventrolateral septum and the anterodorsal and posteroventral medial amygdala, compared with animals allowed to copulate but that did not reach sexual satiety, and decreased c-Fos density in the piriform cortex. These results suggest that the network that underlies sexual satiety is different from that which regulates copulation.

Increased estrogen receptor alpha immunoreactivity in the forebrain of sexually satiated rats.

Estrogen receptor alpha (ERalpha) participates in the neuroendocrine regulation of male sexual behavior, primarily in brain areas located in the limbic system. Males of many species present a long-term inhibition of sexual behavior after several ejaculations, known as sexual satiety. It has been shown that androgen receptor density is reduced 24 h after a single ejaculation or mating to satiety, in the medial preoptic area, nucleus accumbens and ventromedial hypothalamus. The aim of this study was to analyze if the density of ERalpha was also modified 24 h after a single ejaculation or mating to satiety. Sexual satiety was associated with an increased ERalpha density in the anteromedial bed nucleus of the stria terminalis (BSTMA), ventrolateral septum (LSV), posterodorsal medial amygdala (MePD), medial preoptic area (MPA) and nucleus accumbens core (NAc). A single ejaculation was related to an increase in ERalpha density in the BSTMA and MePD. ERalpha density in the arcuate (Arc) and ventromedial hypothalamic nuclei (VMN), and serum estradiol levels remained unchanged 24 h after one ejaculation or mating to satiety. These data suggest a relationship between sexual activity and an increase in the expression of ERalpha in specific brain areas, independently of estradiol levels in systemic circulation.

Facilitating antidepressant-like actions of estrogens are mediated by 5-HT1A and estrogen receptors in the rat forced swimming test.

Previous studies have shown that 17beta-estradiol (E2) induces antidepressant-like actions per se and potentiates those produced by fluoxetine (FLX) in the forced swimming test (FST). The aim of the present work was to explore the participation of serotonin 1A receptors (5-HT1A) and estrogen receptors (ERs) in the antidepressant-like actions of E2, FLX or their combination in the FST. Although all antidepressants reduce behavioral immobility, antidepressants that modulate serotonergic neurotransmission increase swimming behavior whereas those that modulate the catecholaminergic neurotransmission increase climbing behavior. Thus, using this animal model, it is possible to infer which neurotransmitter system is modulating the action of an antidepressant compound. Ovariectomized female Wistar rats were used in all experiments. In the first experiment, an effective dose of E2 (10 microg/rat, -48 h) was combined with several doses (0.5, 1.0 and 2 mg/kg) of RU 58668 (a pure ER antagonist) 48 h previous to the FST. The second experiment evaluated the action of (1 mg/kg, -48 h or -23, -5 and -1 h) WAY 100635 (5-HT1A receptor antagonist) on the antidepressant-like action of FLX (10 mg/kg, -23, -5 and -1 h). In the third experiment, the effect of RU 58668 (2 mg/kg, -48) or WAY 100635 (1 mg/kg, -48 h) on the antidepressant-like action of the combination of a sub-optimal dose of E2 (2.5 microg/rat, -48 h) plus a non-effective dose of FLX (2.5 mg/kg, -23,-5 and -1 h) was evaluated. The results showed that RU 58668, the antagonist to the ER, canceled the antidepressant-like action of E2 in a dose-dependent manner. The antagonist to the 5-HT1A receptor blocked the antidepressant action of FLX only when administered simultaneously with FLX, i.e. -23, -5 and -1 h before the FST. Finally, the administration of both RU 58668, and WAY100635 canceled the antidepressant-like action of the combination of E2/FLX. These results imply that both 5-HT1A receptors and ERs participate in the facilitating actions of E2 on the antidepressant-like action of FLX in the FST.

Comparative analysis of immunoreactive cells for androgen receptors and oestrogen receptor alpha in copulating and non-copulating male rats.

In some species, including gerbils, guinea pigs, mice, rams and rats, some apparently normal males fail to mate. These kinds of animals have been named 'noncopulating (NC)'. The cause of this behavioural deficit is unknown. The present study aimed to determine whether NC male rats have alterations in the amount of androgen (AR) and oestrogen receptor alpha (ERalpha) in a neuronal circuit important for the control of male sexual behaviour; the vomeronasal projection pathway. We evaluated the number of AR and ERalpha immunoreactive (AR-IR and ERalpha-IR) cells in the accessory olfactory bulb (AOB), the bed nucleus of the stria terminalis (BNST), the anterior-dorsal medial amygdala (MeAD), the posterior dorsal amygdala (MePD) and the medial preoptic area (MPOA). The results demonstrate that the number of AR-IR cells in NC males was significantly higher compared to copulating (C) males in the MePD, but no significant differences were found in any of the other structures analysed. ERalpha-IR cells were more abundant in NC than in C males in the MeAD and the MePD. However, in the MPOA the number of ERalpha-IR cells was significantly reduced in NC males. No significant differences were found in the AOB or in the BNST. A similar pattern of results was observed when regions within these structures that are activated by Fos expression, on mating or exposure to sexually relevant cues were analysed. The differences in the number of AR and ER in particular brain areas could be associated with alterations in sexual behaviour as well as partner and olfactory preference for receptive females seen in NC male rats.

Influence of inflammatory nociception on the anxiolytic-like effect of diazepam and buspirone in rats.

RATIONALE: The effect of anxiety on nociception has been evaluated but not that of nociception on anxiety. OBJECTIVE: The study was conducted to analyse the influence of nociception on basal levels of anxiety-like behaviour and on the action of anxiolytic drugs. METHODS: Nociception was induced by an intra-articular injection of uric acid at 3.75 or 7.5%. Experimental anxiety was determined in the rat burying behaviour and the elevated plus maze tests. To separate specific anxiety-related drug actions, a spontaneous ambulatory test was included. The anxiolytics, buspirone (2.5 and 5.0 mg/kg, i.p.) and diazepam (0.5, 1.0 and 2.0 mg/kg, i.p.), were used. RESULTS: In the nociception test, the pain-induced functional impairment rat model, uric acid at 3.75 and 7.5% had an effect of around 35 and 75%, respectively. Uric acid (UA) at the lower dose (3.75%) lacked an effect on burying behaviour but significantly increased the time spent and number of entries to the open arms; the higher UA dose (7.5%) produced a significant increase in the time spent and number of entries to the open arms and a statistically significant reduction in cumulative burying. Diazepam and buspirone produced a clear dose-dependent reduction in cumulative burying. In the plus maze, diazepam also induced an increase in the time spent and number of entries to the open arms. In the burying behaviour test, rats with a mild level of nociception (uric acid at 7.5%) were insensitive to the anxiolytic-like effect of these anxiolytic drugs. In the plus maze test, the anxiolytic-like effect of diazepam (1.0 mg/kg) was blocked under both levels of nociception. CONCLUSIONS: These data demonstrate that nociception modifies the response to anxiolytic drugs. The role of factors with anxiogenic properties produced during inflammation, which may modify diazepam and buspirone effects, is discussed.

Experimental anxiety in the black and white model in cycling, pregnant and lactating rats.

This study demonstrates changes in experimental anxiety assessed in the black and white paradigm during various reproductive states of female rats. Low levels of experimental anxiety were observed during late proestrus and on day 17 of gestation, stages related to high progesterone (P) levels. In estrus, metestrus, diestrus and on day 21 of gestation, stages characterized by low P concentrations, high levels of experimental anxiety, similar to those exhibited by ovariectomized females, were found. No changes in experimental anxiety were observed on day 8 of lactation compared to ovariectomized females. These data are discussed from the standpoint of the putative anxiolytic-like effect of progestins.

Age differences in the sensitivity to clomipramine in an animal model of obsessive-compulsive disorder.

RATIONALE: Subtypes of obsessive-compulsive disorder (OCD) related to age could determine differential response to treatment. OBJECTIVES: To explore possible age differences in the effect of clomipramine in an animal model of OCD. METHODS: The deficits on spontaneous alternation produced by 8-OH-DPAT and the preventing actions of clomipramine, desipramine and WAY 100635 were compared between young and adult rats. RESULTS: No age differences were found in spontaneous alternation. The 5-HT(1A) agonist, 8-OH-DPAT (0.031, 0.125, 0.5 and 2.0 mg/kg, -15 min) produced perseveration in young and adult rats. However, young rats were sensitive to a lower dose of 8-OH-DPAT. Clomipramine (10 mg/kg per three administrations) completely prevented the action of 8-OH-DPAT (0.5 mg/kg) in adult rats. However, this treatment as well as higher doses (15 mg/kg 3 administrations) or injected for longer periods (10 mg/kg 5 administrations) produced weak protective effects (versus 0.125 mg/kg 8-OH-DPAT) or had no action (versus 0.5 mg/kg 8-OH-DPAT) in young animals. WAY 100 635 (0.5 mg/kg) blocked the action of 8-OH-DPAT (0.5 mg/kg) in both young and adult rats. Desipramine (10 mg/kg/3 administrations) lacked of a preventive effect on the 8-OH-DPAT (0.5 mg/kg) action. This result indicated that the 5-HT(1A) receptor is involved in the deficits on spontaneous alternation produced by 8-OH-DPAT. CONCLUSIONS: The present data shows important age differences in the effect of clomipramine in a model of OCD. Such differences could be relevant for the age variations in the response to treatment in clinical practice.

Diazepam and progesterone produce sexually dimorphic actions on the rat EEG: role of the neonatal sexual differentiation process.

This study was designed to analyse if the effect of diazepam or progesterone on the wakeful rat EEG vary according to sex and neonatal sexual differentiation. Diazepam or progesterone was administered to males, females, neonatally castrated males and neonatally virilised females. Comparisons of drug actions were made versus baseline values. Both compounds produced clear sexual dimorphic responses, males being more sensitive than females. In normal males and neonatally virilised females diazepam produced a clear increase in the absolute power of fast frequencies. In normal females and neonatally castrated males this anxiolytic only produced a moderate increase in the absolute power of the beta 2 band. Regarding interparietal correlation, diazepam produced an increase in males in the alpha, beta 1 and beta 2 bands, while in females this drug caused a reduction in the same bands. Neonatally castrated males or virilised females showed an intermediate pattern. These data suggest that sexual dimorphism in diazepam action depends upon neonatal sexual differentiation. Progesterone, in contrast with diazepam, produced effects on the EEG that were also sexually dimorphic but independent of the sexual differentiation process. This steroid in males induced an increase in the absolute power of the fast bands of the EEG (alpha, beta 1 and beta 2) accompanied by an increased interparietal correlation of the alpha band. In females, progesterone only reduced the interparietal correlation in the fast theta and alpha bands. Data show similarities between diazepam and progesterone effects on the EEG that are discussed in the light of the anxiolytic-like and hypnotic properties of these compounds. A similar mechanism of action for both substances, involving the GABA(A) receptor, is sustained.