Learning during motherhood: A resistance to stress

Hormonal and emotional responses to stress are diminished during pregnancy and the postpartum period. However, the effects of stress on learning during these stages of the female life span have not been examined. In previous studies, we have reported that exposure to an acute stressful event reduces classical eyeblink conditioning 24 h later in adult virgin female rats that are experiencing an ovarian cycle. Here we show that conditioning during late pregnancy was similarly reduced by stressful experience. However, conditioning in postpartum females was unaffected by stressor exposure. The resistance to stress during the postpartum period was evident as early as 2 days after parturition and persisted until the late postpartum period, just prior to weaning. Postpartum conditioning was unresponsive to numerous types of stressors, including brief inescapable tailshocks, swim stress, and exposure to a male intruder. The resistance to stress appears to be dependent on the presence of the offspring, because the impairment in conditioning returned when postpartum females were separated from their pups. Moreover, the resistance to stress occurred in virgin females that behaved maternally after being exposed to young pups for several days. Together, these data suggest that the presence of offspring and the nurturing and care-giving activities that they elicit protect females from the adverse effect of stress on processes involved in learning and memory.     

Dysregulation of neonatal hippocampal cell genesis in the androgen insensitive Tfm rat

The first two weeks of life are a critical period for hippocampal development. At this time gonadal steroid exposure organizes sex differences in hippocampal sensitivity to activational effects of steroids, hippocampal cell morphology and hippocampus dependent behaviors. Our laboratory has characterized a robust sex difference in neonatal neurogenesis in the hippocampus that is mediated by estradiol. Here, we extend our knowledge of this sex difference by comparing the male and female hippocampus to the androgen insensitive testicular feminized mutant (Tfm) rat. In the neonatal Tfm rat hippocampus, fewer newly generated cells survive compared to males or females. This deficit in cell genesis is partially recovered with the potent androgen DHT, but is more completely recovered following estradiol administration. Tfm rats do not differ from males or females in the level of endogenous estradiol in the neonatal hippocampus, suggesting other mechanisms mediate a differential sensitivity to estradiol in male, female and Tfm hippocampus. We also demonstrate disrupted performance on a hippocampal-dependent contextual fear discrimination task. Tfm rats generalize fear across contexts, and do not exhibit significant loss of fear during extinction exposure. These results extend prior reports of exaggerated response to stress in Tfm rats, and following gonadectomy in normal male rats.     

Ontogeny and sexual dimorphism of estradiol-2-hydroxylase activity in rat liver microsomes

A radio-enzymatic method was used to measure the activity of estradiol-2-hydroxylase in liver microsomes of male and female Wistar rats, ranging in age from 10 to 63 days. In pre-pubertal rats (10-30 days) the Vmax increased, but revealed no sex differences. After 30 days of age, however, it decreased in females. In males, on the other hand, it increased still further, reaching a maximum in adulthood. The apparent Km showed no significant sex differences in pre-pubertal rats, but appeared to decline after puberty in females. In females puberty was also associated with the appearance of important changes in the kinetic properties of estradiol-2-hydroxylase. These changes were reflected in hyperbolic Lineweaver-Burk plots. Hill plots of this data gave straight lines with slopes significantly less than one--indicating negative cooperativity. Alternatively the hyperbolic Lineweaver-Burk plots could mean that the enzyme consists of more than one form, which act on the same substrate, but with different affinities. It is concluded that development in female Wistar rats is associated with important qualitative changes in the kinetic properties of estradiol-2-hydroxylase and that factors which become operative during puberty play a key role in initiating these changes.     

Sexual dimorphism of the intracellular heat shock protein 72 response.

The majority of previous work examining stress responses has been done in males. Recently, it has become clear that the impact of stressor exposure is modulated by sex. One stress response that may be affected by sex is the induction of intracellular heat shock protein (HSP) 72, which is a stress- responsive molecular chaperone that refolds denatured proteins and promotes cellular survival. The following study compared HSP72 in males and females and also examined whether the estrous cycle altered HSP72 induction in females. We hypothesized that females compared with males would have a constrained HSP72 response after an acute stressor and that the stress-induced HSP72 response in females would fluctuate with the estrous cycle. Male and female F344 rats were either left in their home cage or exposed to acute tail-shock stress (8-10/group). Immediately following stressor, trunk blood was collected and tissues were flash frozen. Vaginal smear and estrogen enzyme immunoassay were used to categorize the phase of estrous. Results show that female rats had a greater corticosterone response than males, that both males and females exhibit a stress-induced release of progesterone, and that males and females had equal levels of stress-induced circulating norepinephrine. Sexual dimorphism of the HSP72 (ELISA) response existed in pituitary gland, mesenteric lymph nodes, and liver such that female rats had an attenuated HSP72 response compared with males after stress. The adrenal glands, spleen, and heart did not exhibit sexual dimorphism of the HSP72 response. The estrous cycle did not have a significant effect on basal or stress-induced HSP72 in females.     

Evidence that physiologic levels of circulating estrogens and neonatal sex-imprinting modify postpubertal hepatic microsomal 3-hydroxy-3-methylglutaryl coenzyme a reductase activity

Ontact, but sham-operated female rats had 2- to 3-fold higher levels of hepatic 3-hydroxy-3-methylglutary CoA reductase activity than their male couterparts (15–21.5 vs. 6.7–8.7 nmol mevalonate/mg protein per h). The activity of the hepatic enzyme declined to about the same relative degree (40–60%) in male and female rats that were gonadectomized after puberty (53 days of age) and killed 5 weeks later. Implantion of silastic capsules containing 17β-estradiol increased the level of hepatic 3-hydroxy-3-methylglutaryl CoA reductase to levels found in sham-operated controls. In rats that were gonadectomized in infacny (12 h old) and killed 7–8 weeks later, the level of enzyme activity was not altered in females, but it was increased from 60–240% in males. Consequently, following neonatal gonadectomy, male-female differences in enzyme activity were no longer apparent. Implantation of islastic capsules containing estradiol in neonatally gonadectomized rats resulted in a doubling of enzyme activity in both males and females. Ovariectomy reduced plasma estrogen levels, but implantation of estradiol in gonadectomized males and behavioral characteristics. We found in confirmation of an earlier study [20], that in comparison to females, the higher body weight of males and presumably their increased food intake, was also dependent on sex imprinting that occured prior to birth. This observation takes on particular significance in view of the recent report that the amount and quality of food eaten during infancy exerted a long lasting effect on the post-pubertal regulation of 3-hydroxy-3-methyl-glutaryl CoA reductase activity [21,22] and bile acid synthesis [23]. Thus, while a direct effect of neonatal sex imprinting on the regulation of 3-hydroxy-3-methyglutaryl CoA reductase activity is still possible, more indirect mechanisms [24] should also be considered.     

The effect of sex steroid hormones on interhemispheric asymmetry in rats]

The effect of gonadectomy and sex-steroid hormones treatment on functional interhemispheric asymmetry to the reaction of pain cry avoidance of another species (emotional reactions) and motor and exploratory activity of open-field behavior in Wistar rats of 3 months old has been investigated. A spreading depression technique for hemisphere inactivation has been used. The hemispheric asymmetry of the reactions in intact rats was characterized by sex dimorphism; the left hemisphere dominated to a great extent in males than in females under the control of emotional reactions; in motor and exploratory activity in open-field behavior of rats the left hemisphere dominated in males and the right one--in female. In both sexes the neonatal gonadectomy levelled the interhemispheric differences in reactions under investigation. The following treatment of females with estradiol and males with testosterone didn't restore the asymmetry. After the castration at the age of 3 months the correlation between the size and direction of interhemispheric differences became reverse. The treatment of females with testosterone and males with estradiol both castrated in adulthood restored the interhemispheric asymmetry in males and had no effect in females. The treatment of intact rats with hormones of opposite sex led to the enhancement of left hemisphere dominance in motor and exploratory activity in males and levelled the asymmetry in females. It has been shown that in adult rats sex-steroids effect predominantly the right hemisphere.     

Sexual dimorphism of the human mandible and its association with dental development

The present study investigates whether the human mandible is sexually dimorphic during early postnatal development and whether early dimorphic features persist during subsequent ontogeny. We also examine whether mandibular dimorphism is linked to dimorphism of dental development. Dense CT-derived mandibular meshes of 84 females and 75 males, ranging from birth to adulthood, were analyzed using geometric morphometric methods. On the basis of the specimen's chronological ages and mineralization stages of the deciduous and permanent teeth, we compute dental age as proxy for dental development by the additive conjoint measurement method. By birth, males have, on average, more advanced age-specific shapes than females. However, sex differences decrease quickly as females catch up via a different association between shape and size. This leads to an almost complete reduction of sexual dimorphism between the ages of 4 and 14. From puberty to adulthood, males are characterized by allometric shape changes while the shape of the female mandible continues to change even after size has ceased to increase. Dimorphism of dental maturation becomes visible only at puberty. Sexual dimorphism, concentrated at the ramus and the mental region during the earliest ontogenetic stages and again at adulthood, is not associated with the development of the teeth. At puberty there is a simultaneous peak in size increase, shape development, and dental maturation likely controlled by the surge of sex hormones with a dimorphic onset age. We argue that the infant and adult dimorphism of the mental region may be associated with the development of supralaryngeal structures.     

Perinatal exposure to progesterone, estradiol, or mifepristone affects sexual differentiation of behavior in opossums (Monodelphis domestica)

The effects of perinatal exposure to progesterone (P) and estradiol (E) on sexual differentiation of behavior and morphology were examined by treating male and female gray short-tailed opossums on postnatal day 8 with progesterone alone (P), P plus estradiol (E) (PE), the P receptor antagonist mifepristone/RU486 (MIF), or corn oil control (C) and gonadectomizing them before puberty. When given female hormone replacement therapy in adulthood and tested with intact stimulus males, MIF animals showed less female-typical aggressive threat behavior than animals in other treatment groups. Stimulus males scent marked in more tests involving females than males and in more tests involving MIF animals than animals in other treatment groups. Body weight was lower in females than in males and was lower in MIF animals than in animals in other treatment groups, and P females failed to show female-typical genital locks after copulation. Sexual receptivity was similar in males and females and, while not decreased by any perinatal hormone treatment, was higher in PE males than in animals of either sex in any treatment group. These findings suggest that perinatal exposure to P is associated with the organization of feminine threat behavior and the defeminization of attractivity, body weight and genital anatomy in this marsupial. Reasons for these findings and for why female sexual receptivity is enhanced by perinatal exposure to exogenous E only in an endogenous masculine environment are discussed.     

Cues that Elicit Ultrasounds from Adult Male Mice

Adult male mice (Mus musculus) which have a prior history ofexperience with other adult male and adult female mice readilyproduce 70 kHz ultrasonic vocalizations in the presence of urinefrom adult females but not in the presence of urine from adultmales. Urine from immatures of either sex does not elicit ultrasoundsfrom socially experienced adult males. The ultrasound elicitingpotency of adult male urine was not improved substantially followingcastration of adult males, injection of testosterone propionateto castrated adult males, administration of estradiol benzoateto castrated adult males, or neonatal castration. Ovarian hormonesdo not appear to be necessary for either the appearance at puberty,or the maintenance during adulthood, of the ultrasound elicitingcues of female urine. Stage of estrus did not have a major modulatingeffect on urinary cues eliciling male ultrasounds. Treatmentsthat did not substantially reduce the signal value of adultfemale urine include ovariectomy before or after puberty, ovariectomywith adrenalectomy, and neonatal administration of testosterone.The administration of testosterone to ovariectomized adult females,and hypophyseclomy, virtually eliminated the ability of urinefrom adult females to elicit ultrasounds from socially experiencedadult males. The implication of pituitary hormones in the modulationof female urinary cues thai elicit ultrasounds is particularlyinteresting since pituitary factors are also implicated in theproximal causation of postparturient maternal aggression, whichadult male ultrasounds may function to moderate.     

Relevance of stress and female sex hormones for emotion and cognition

There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders.     

Effects of early experience on female behavioural and reproductive development in rhesus macaques

A growing body of research on humans suggests that exposure to a stressful family environment or father absence from home during childhood is associated with early female puberty and greater interest in infants among adolescent girls. This effect may be mediated by early exposure to harsh and inconsistent maternal care, but the mechanisms by which maternal care affects female reproductive maturation are not known. The present study reports sex differences in interest in infants among juvenile rhesus macaques similar to those observed in human adolescents. Furthermore, juvenile females that were exposed to harsh and inconsistent maternal care in infancy showed higher interest in infants than controls. Evidence from cross-fostered females indicated that these effects resulted from early experience and not genetic inheritance from the mother. There were no significant differences in female age at first conception in relation to the quality of maternal care received during infancy. Macaque females exposed to harsh and inconsistent maternal care in infancy tended to have higher cortisol responses to stress and to corticotropin-releasing hormone than controls in the first three years of life. Furthermore, females with higher cortisol responses to stress exhibited higher interest in infants. These findings suggest that some of the effects of early parental care on female reproductive maturation may be mediated by developmental changes in the activity of the hypothalamic-pituitary-adrenal axis.     

Anxiety-like behaviors in adulthood are altered in male but not female rats exposed to low dosages of polychlorinated biphenyls in utero

Exposure to polychlorinated biphenyls (PCBs), a class of endocrine-disrupting chemicals, can result in altered reproductive behavior in adulthood, especially when exposure occurs during critical periods of brain sexual differentiation in the fetus. Whether PCBs alter other sexually dimorphic behaviors such as those involved in anxiety is poorly understood. To address this, pregnant rat dams were injected twice, on gestational days 16 and 18, with the weakly estrogenic PCB mixture Aroclor 1221 (A1221) at one of two low dosages (0.5 mg/kg or 1.0 mg/kg, hereafter 1.0 and 0.5), estradiol benzoate (EB; 50 μg/kg) as a positive estrogenic control, or the vehicle (3% DMSO in sesame oil). We also conducted a comprehensive assessment of developmental milestones of the F1 male and female offspring. There were no effects of treatment on sex ratio at birth and age at eye opening. Puberty, assessed by vaginal opening in females and preputial separation in males, was not affected in females but was advanced in males treated with A1221 (1.0). Males and females treated with A1221 (both dosages) were heavier in early adulthood relative to controls. The earliest manifestation of this effect developed in males prior to puberty and in females slightly later, during puberty. Anxiety-like behaviors were tested using the light:dark box and elevated plus maze tests in adulthood. In females, anxiety behaviors were unaffected by treatment. Males treated with A1221 (1.0) showed reduced indices of anxiety and increased activity in the light:dark box but not the elevated plus maze. EB failed to replicate the phenotype produced by A1221 for any of the developmental and behavioral endpoints. Collectively, these results indicate that PCBs increase body weight in both sexes, but their effects on anxiety-like behaviors are specific to males. Furthermore, differences between the results of A1221 and EB suggest that the PCBs are likely acting through mechanisms distinct from their estrogenic activity.     

Body development and puberty in spontaneously hypertensive rats

The body growth and the onset of puberty in spontaneously hypertensive rats (SHR) and in normotensive controls (WKY) have been studied. In female rats the onset of puberty was determined by both the age and the body weight at which the vaginal opening and first estrus appeared, as well as the ability of estradiol and progesterone to induce pituitary LH release. For this purpose females were injected with estradiol benzoate (0.1 mg/kg) and progesterone (1 mg/rat). Control animals received only oil vehicle. In male rats, puberty was assessed by studying the age and body weight at the time of balano-preputial separation. In another experiment, SH and WKY rats were decapitated on day 30 to determine FSH, LH, PRL, GH and testosterone plasma levels in males and FSH and LH in females. The results obtained show: a) A greater body weight, at all the ages studied (every 4 days between days 28 and 92) in SHR animals. b) A delay in vaginal opening and first estrus presentation in SHR females. c) Absence of spontaneous LH peaks in WKY females. d) Advancement in balano-preputial separation in SHR males and e) Higher plasma FSH levels in SHR males than in WKY males, without differences in other hormones.     

Aggressive behavior in female golden hamsters: development and the effect of repeated social stress

In male golden hamsters, agonistic behavior matures during puberty, changing from play fighting to adult-like aggression. In addition, this transition is accelerated by repeated social subjugation early in puberty. However, little is known about the development of agonistic behavior in females. In the present study, we compared the development of agonistic behavior in male and female golden hamsters. Furthermore, we also tested the effects of repeated social subjugation on the development of agonistic behavior during puberty. Hamsters were tested for agonistic behavior in the presence of a smaller intruder at different intervals during puberty. Several observations were made. First, the frequency of attacks remained stable in females, while varying in males. Second, the transition from play fighting to adult-like aggression occurred at earlier time periods in females than in males. Finally, a clear transitional period marked by attacks focused on the flanks was observable in males around mid-puberty. However, this transitional period was not apparent in females. In addition, juvenile females were exposed to aggressive adult males or females. In both cases, repeated exposure to stress had no statistically significant effect on the development of agonistic behavior. After 2 weeks of subjugation, exposure to aggressive adults had no effect on serum cortisol levels, indicating that juvenile females habituate to repeated social stress. These data show significant sex differences in the development of agonistic behavior and adaptation to repeated stress in juvenile golden hamsters.     

Impact of pubertal and adult estradiol treatments on cocaine self-administration

Estradiol is thought to play a critical role in the increased vulnerability to psychostimulant abuse in women. Sex differences in the ability of estradiol to influence cocaine self-administration in adult rats have been hypothesized to depend upon pubertal estradiol exposure. The current study investigated whether the presence of gonadal hormones during puberty affected cocaine self-administration behavior and its sensitivity to adult estradiol treatment in male and female Sprague–Dawley rats. Subjects were gonadectomized or SHAM-operated at postnatal day (PD) 22, and received either OIL or estradiol benzoate (EB) during the approximate time of puberty (PD27 to PD37). Adult rats were subsequently treated with either EB or OIL 30 min before cocaine self-administration (0.3 mg/kg/inf) in order to examine the effects of pubertal manipulations on the estradiol sensitivity of acquisition on a fixed ratio (FR) 1 schedule, total intake on a FR5 schedule and motivation on a progressive ratio schedule. Adult EB treatment only affected cocaine self-administration in females, which is consistent with previous research. Adult EB treatment enhanced acquisition in all females irrespective of puberty manipulations. All females, except those treated with EB during puberty, displayed increased cocaine intake following adult EB treatment. Adult EB treatment only enhanced motivation in females that were intact during puberty, whereas those treated with EB during puberty showed reduced motivation. Therefore, the sensitivities of different self-administration behaviors to adult estradiol treatment are organized independently in females, with pubertal estradiol exerting a greater influence over motivational processes, and negligible effects on learning/acquisition.     

Prenatal testosterone exposure leads to hypertension that is gonadal hormone-dependent in adult rat male and female offspring

Prenatal testosterone exposure impacts postnatal reproductive and endocrine function, leading to alterations in sex steroid levels. Because gonadal steroids are key regulators of cardiovascular function, it is possible that alteration in sex steroid hormones may contribute to development of hypertension in prenatally testosterone-exposed adults. The objectives of this study were to evaluate whether prenatal testosterone exposure leads to development of hypertension in adult males and females and to assess the influence of gonadal hormones on arterial pressure in these animals. Offspring of pregnant rats treated with testosterone propionate or its vehicle (controls) were examined. Subsets of male and female offspring were gonadectomized at 7 wk of age, and some offspring from age 7 to 24 wk received hormone replacement, while others did not. Testosterone exposure during prenatal life significantly increased arterial pressure in both male and female adult offspring; however, the effect was greater in males. Prenatal androgen-exposed males and females had more circulating testosterone during adult life, with no change in estradiol levels. Gonadectomy prevented hyperandrogenism and also reversed hypertension in these rats. Testosterone replacement in orchiectomized males restored hypertension, while estradiol replacement in ovariectomized females was without effect. Steroidal changes were associated with defective expression of gonadal steroidogenic genes, with Star, Sf1, and Hsd17b1 upregulation in testes. In ovaries, Star and Cyp11a1 genes were upregulated, while Cyp19 was downregulated. This study showed that prenatal testosterone exposure led to development of gonad-dependent hypertension during adult life. Defective steroidogenesis may contribute in part to the observed steroidal changes.     

Ovarian hormones act early in development to feminize adult open-field behavior in the rat

Three experiments were done to investigate the feminizing effect of prepubertal ovarian hormones on the development of adult sex differences in open-field behavior in the rat. Gonadectomy at either 1 or 8 days of age, but not at 23 days or later, disrupted the normally high levels of activity found in adult females. Exposure of Day 1 gonadectomized female and male rats to low doses of exogenous estradiol between Days 10 and 20 led to higher levels of adult activity than did oil treatment. Finally it was shown that low doses of estradiol had similar effects on open-field scores whether given between Days 10 and 20 or between Days 30 and 40, whereas exposure of Day 1 gonadectomized females to a high dose of estradiol as late as 10 days of life appeared to suppress adult open-field activity. It was concluded that estrogens given during the period prior to weaning can have a feminizing effect on adult open-field behavior and that the sex difference normally observed in adult rats is dependent in part on the presence of the ovaries during a period after birth.     

Paradoxical effects of maternal stress on fetal steroids and postnatal reproductive traits in female mice from different intrauterine positions

We examined effects of maternal stress on prenatal serum concentrations of testosterone and estradiol and on postnatal reproductive traits in female mice from different intrauterine positions. On Day 18 of fetal life, control females positioned in utero between two male fetuses (2M females) had higher concentrations of testosterone and lower concentrations of estradiol in serum than control female fetuses located between two females (0M females). Control females positioned between a male and a female fetus (1M females) had intermediate levels of both hormones. Prior intrauterine position in control females accounted for differences in genital morphology (length of the anogenital separation) at birth and length of estrous cycles during adulthood. Maternal stress eliminated these postnatal differences due to prior intrauterine position: all 0M, 1M, and 2M female offspring of stressed mothers exhibited postnatal traits that were indistinguishable from those of control 2M females. Maternal stress resulted in an increase of over 1 ng/ml in serum testosterone in all female fetuses; the magnitude of the increase was similar for 0M, 1M, and 2M females. There was no effect of maternal stress on serum concentrations of estradiol in 0M and 2M female fetuses. Maternal stress resulted in a dramatic change in the postnatal traits of 0M females, whereas 2M females showed no change. Since the effect of maternal stress on sex steroids was similar among fetuses from different intrauterine positions but postnatal response to maternal stress varied by intrauterine position, other components of the endocrine system may mediate effects of maternal stress on these postnatal characteristics.     

Effects of testosterone and estrogen on hepatic levels of cytochromes P450 2C7 and P450 2C11 in the rat.

The effects of exogenous hormone treatment on the expression of cytochromes P450 2C7 and P450 2C11 were studied in neonatally gonadectomized and sham-operated male and female rats. Hepatic levels of cytochrome P450 2C7 were found to be two- to threefold higher in intact adult female versus male rats. Neonatal gonadectomy resulted in a reversal of the relative cytochrome P450 2C7 levels in male and female animals at maturity. Expression of this isozyme was restored in ovariectomized females by estradiol treatment. Furthermore, neonatal and/or pubertal administration of estradiol to intact male rats induced cytochrome P450 2C7 to adult female levels. On the other hand, administration of testosterone at all times examined had no effect in intact female rats, but decreased cytochrome P450 2C7 to normal levels in neonatally castrated males treated during adulthood. Neonatal testosterone treatment also increased hepatic cytochrome P450 2C7 content in both ovariectomized females and intact males. These results indicate that estrogen is required for full expression of cytochrome P450 2C7 while the effect of testosterone is ambiguous. In comparison, neonatal gonadectomy of male rats abolished the adult expression of cytochrome P450 2C11. Normal levels were restored only by treatment with testosterone during adulthood. Neonatal testosterone treatment did not induce cytochrome P450 2C11 levels in gonadectomized rats of either sex. In contrast, neonatal estrogen treatment suppressed cytochrome P450 2C11 expression in intact adult male rats to the same extent as neonatal castration. These results indicate that androgen exposure during the adult, and not the neonatal, phase is essential for full expression of cytochrome P450 2C11.     

Prenatal Amphetamine-Induced Dopaminergic Alteration in a Gender- and Estrogen-Dependent Manner

Prenatal exposure to amphetamine induces changes in dopamine receptors in mesolimbic areas and alters locomotor response to amphetamine during adulthood. Sex differences have been reported in amphetamine-induced brain activity and stress sensitivity. We evaluated the effects of prenatal amphetamine exposure on locomotor activity, dopamine receptors and tyrosine hydroxylase mRNA expression in nucleus accumbens and caudate-putamen in response to amphetamine challenge in adult female and male rats. The role of estrogen in the response to restraint stress was analyzed in ovariectomized, prenatally amphetamine-exposed rats. Pregnant rats were treated with d-amphetamine during days 15–21 of gestation. Nucleus accumbens and caudate-putamen were processed for mRNA determination by real-time PCR. In nucleus accumbens, higher mRNA dopamine (D3) receptor expression was found in basal and d-amphetamine-challenge conditions in female than male, and prenatal amphetamine increased the difference. No sex differences were observed in caudate-putamen. Basal saline-treated females showed higher locomotor activity than males. Amphetamine challenge in prenatally amphetamine-exposed rats increased locomotor activity in males and reduced it in females. In nucleus accumbens, estrogen diminished mRNA D1, D2 and D3 receptor expression in basal, and D1 and D3 in ovariectomized stressed rats. Estrogen prevented the increase in tyrosine hydroxylase expression induced by stress in ovariectomized prenatally exposed rats. In conclusion, estrogen modulates mRNA levels of D1, D2 and D3 receptors and tyrosine hydroxylase expression in nucleus accumbens; prenatal amphetamine-exposure effects on D3 receptors and behavioral responses were gender dependent.