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Official websites use. Share sensitive information only on official, secure websites. Correspondence to: Mohammad Taghi Joghataei, E-mail: joghataeimt iums. Recent evidence demonstrates that female subjects show exaggerated responses to 3,4-methylenedioxymethamphetamine MDMA compared with males. The aim of our study was to evaluate sex differences and the role of endogenous gonadal hormones on the effects of MDMA. Learning and memory were assessed using the Morris water maze MWM. The expression of Bax and Bcl-2 in the hippocampus was detected by Western blotting. Behavioral analysis showed that MDMA led to memory impairment in both male and female rats. The female rats showed more sensitivity to impairment than the males, as assessed using all the memory parameters in the MWM. Ovariectomy attenuated the MDMA-induced memory impairment. By contrast, orchiectomized rats showed more impairment than MDMA-treated intact male rats. Bcl-2 and Bax were down-regulated and up-regulated in MDMA-treated male and female rats, respectively. In summary, female rats showed exaggerated responses to the effects of MDMA and this may be explained by endogenous gonadal hormones. MDMA influences serotonergic, dopaminergic and noradrenergic nerve endings in the brain, showing greater affinity for the serotonergic system. It causes an increase in synaptic serotonin levels and binds to the serotonin transporter. At high doses, MDMA produces an acute depletion in serotonin in serotonergic endings at 4—6 h followed by a recovery by 24 h Schmidt, The neurotoxic effects of MDMA are relatively well described in humans and animals. For example, it has been shown that MDMA causes feelings of closeness accompanied by enhanced emotion and increased blood pressure, heart rate and body temperature, as well as many other effects Steinkellner et al. Exposure to MDMA causes memory impairment and cell death in many regions of the brain Stephenson et al. However, little is known about sex differences related to MDMA-induced neurotoxicity. Studies in humans have described that women report greater thought disturbances, perceptual changes, and fear of loss of body control. By contrast, men experience greater increases in blood pressure Liechti et al. The other sex differences in the response to ecstasy include increased subjective effects in females compared with males, and greater susceptibility to the effects of the drug, more pronounced depression following ecstasy use, and a potential increase in serotonergic neurotoxicity in association with long-term use of MDMA in women Liechti et al. Another study showed greater reduction in 5-hydroxyin-doleacetic acid levels in females than in males McCann et al. There are only a few studies that have described the unequal effects of MDMA in male and female primates. Fitzgerald et al. Babenikova et al. They observed a dose-dependent locomotion-enhancing effect of MDMA both in male and female rats in an elevated plus-maze; this response was exaggerated in female rats and the authors hypothesized that the increased sensitivity of females to the behavioral effects of MDMA can be explained by increased reactivity of the serotonergic and dopaminergic systems Palenicek et al. It is clear that gonadal hormones affect the levels of dopamine and serotonin in the different parts of the brain McEwen, It seems that the possible sex differences in the neurotoxic effects of MDMA may be due to gonadal hormones. To our knowledge, there is no evidence on gender differences in MDMA-induced memory impairment and cell death in animals or on relations between gonadal hormones and MDMA effects. In this study, we evaluated the sex differences in the neurotoxic effects of MDMA and the relationship of these effects with gonadal hormones in Sprague-Dawley rats. Other chemicals were purchased from commercial sources. All experiments were carried out on adult male — g and female — g Sprague-Dawley rats Razi Institute, Iran. All animal surgeries, behavioral tests and experimental protocols were approved by the Ethics Committee of Iran University of Medical Sciences. Two saline-treated intact groups male and female that received normal saline, 1 ml twice daily, IP for 7 days. Two saline-treated gonadectomized groups male and female that received normal saline, 1 ml twice daily, IP for 7 days. One week after their arrival, the saline-treated and MDMA-treated gonadectomized groups underwent bilateral ovariectomy or orchiectomy to remove circulating hormones. The ovaries were typically approached by two separate flank incisions and were gently pulled through the incision with a blunt forceps by grasping the fat pad surrounding the instrument. A hemostat was placed at the boundary between the oviduct and uterus, a ligature was placed just below the hemostat next to the uterus , and a cut was made just above the hemostat. Once the ovary and oviduct had been removed, the hemostat was released and the uterus was returned to the abdomen. Muscles and skin were closed with suture. For orchiectomy, the testis was approached by a single midline incision on the scrotal sac. Both testes were pushed down into the scrotum by gentle pressure on the abdomen. A hemostat was placed below the testes and epididymis across the testicular cord this contains blood vessels and the vas deferens. A ligature was placed below the hemostat and the testes and epididymis were removed with scissors. The hemostat was released and the incision closed in two layers with suture. Gonadectomy also ensured a constant level of gonadal receptor expression within the brain because receptor levels are regulated by hormones Suzuki and Handa, There exist various methods for measuring memory impairments. In this study, therefore, we used the Morris water maze MWM to evaluate spatial memory. Around the room, numerous visual cues e. The pool was divided into four quadrants with four starting locations -northern N , eastern E , southern S and western W , each located at equal distances along the pool rim. An invisible Plexiglas platform 10 cm diameter was located 1 cm below the water in the center of the northern quadrant. The position of the escape platform remained the same for all the animals across the training trials. We trained the animals for three days at approximately the same time — a. Each training day included two blocks of four trials. The time limit for each trial was 90 s. During training, the animals were allowed to swim until they located the hidden platform or until the 90 s had elapsed. All groups were trained from each of the starting positions N, S, E and W. A 30 s period was allowed between trials, which was spent on the platform. Rats were also allowed to rest for 5 min between the two blocks. The day after the last learning trial, each rat was given a single 60 s probe trial and a visible trial. The probe trials were conducted without a platform. In the visible trials, the platform was covered with aluminum foil. A video camera Nikon, Melville, NY, USA linked to a computer was mounted directly above the MWM pool to record, for each rat, the time taken to reach the hidden platform escape latency , the length of the swim path distance traveled , and the percentage of time spent in the target quadrant. After the spatial memory assessment, for immunoblotting of Bax and Bcl-2 proteins, three rats from each group were killed by cervical dislocation and their hippocampi were removed and immediately frozen in liquid N2. Bands were detected by incubation with chromogenic substrate 5-bromochloroindolyl phosphate in the presence of nitroblue tetrazolium. Each Western blot was performed in triplicate. ANOVA of the three training days, showed that the saline-treated groups spent less time in locating the hidden platform escape latency than the MDMA-treated groups. Gonadectomy in saline-treated rats resulted in a non-significant increase in escape latency compared with the saline-treated intact groups. Escape latency was higher in MDMA-treated orchiectomized rats mean There was no significant difference in escape latency in the visible trial session between the treatment and saline groups data not shown. There was no significant difference in the distance traveled in the visible trial session between the treatment and saline groups data not shown. There was no significant interaction between the factors. Bax was more expressed in the MDMA-treated female rats mean Anti-Bcl-2 antibody reacted with 26 KD protein bands Fig. Bcl-2 was expressed more in the saline-treated rats. Bcl-2 was less expressed in the MDMA-treated intact females mean In the present study, we found that the female rats, compared with the male rats, were more sensitive to MDMA toxicity and demonstrated an exaggerated response to MDMA administration. Furthermore, MDMA induced greater responses in orchiectomized rats compared with non-orchiectomized rats, whereas ovariectomy attenuated MDMA-induced neurotoxicity compared with what was observed in non-ovariectomized rats. Consistent with our study, Walker et al. Other sex differences in the response to MDMA have previously been reported and include increased subjective effects in women compared with men Liechti et al. There is growing evidence that females are more susceptible to the effects of drugs of abuse Carroll et al. It has been reported that pharmacological sensitivity to ecstasy is dependent on gonadal hormone changes during the estrous cycle in female rats Bubenikova et al. The estrous cycle comprises the physiological changes that are induced by reproductive hormones in females. Variations in endogenous estrogen levels across the estrous cycle modulate some aspects of memory Warren and Juraska, It has been established that estrogen influences synaptic plasticity in the hippocampus and that gonadectomy results in a loss of post-synaptic dendritic spines of hippocampal neurons of the CA1 region Vedder et al. Spine density varies with the estrous cycle, peaking at the proestrous stage, shortly before ovulation, when serum estradiol concentrations are highest Woolley and McEwen, The mechanism by which MDMA induces greater neurotoxicity in females is likely due to gonadal steroid effects on the serotonergic mechanism through which MDMA acts. A potential increase in serotonergic neurotoxicity in association with long-term use of MDMA has been reported in women Reneman et al. Fedotova and Ordyan suggested that chronic administration of NAN as a 5-HT1A receptor antagonist in adult female rats in the proestrous and estrous phase resulted in the appearance of passive avoidance performance, as distinct from the control animals. The enhanced response in females may reflect a sex-specific receptor up-regulation mediated by estrogen-facilitated 5-HT2 receptor synthesis Kehne et al. Females exhibit increased sensitivity to the anxiolytic effects of 5-HT1A agonists Simerly et al. It has been found that ovarian steroids in different parts of the rat brain affect dopamine and serotonin levels McEwen, In the present study, removal of the source of gonadal hormones resulted in an increase in neurotoxicity in male rats, whereas in female rats it attenuated MDMA-induced spatial learning impairment and cell death. Taken together, these findings seem to show that gonadal hormones affect MDMA-associated neurotoxicity. Gonadectomy results in an increase in cellular 5-HT mRNA content in the cortex, hippocampus, hypothalamus and amygdala, where the androgen receptors are abundant Simerly et al. Testosterone inhibits the serotonergic function that is responsible for the enhanced serotonergic responsivity seen in female rats Fischette et al. Zhang et al. Studies have shown that estradiol, a metabolite of testosterone, modulates neuronal 5-HT content and receptor binding as well as receptor mRNA levels Sumner and Fink, Developmentally, 5-HT appears early and exerts widespread effects on brain morphogenesis and synaptogenesis Kobe et al. Gonadal steroids may therefore alter brain morphology and function by regulating the development of the 5-HT system, as well as by regulating neural cell death or apoptosis Dodson and Gorski, Sexual dimorphism in brain circuitry might mediate the gender-related differences in physiology or behavior, depending upon the brain region involved. The serotonergic system plays a role in the regulation of affective state, learning and memory, all of which have been demonstrated to differ according to gender, and disturbances of which characterize affective disorders in humans Price et al. Overall, we observed impairment in spatial memory and apoptosis following MDMA treatment both in male and female rats. The female rats were more sensitive to the MDMA effects than the males. The increased sensitivity of the females can be explained by an increased reactivity of the serotonin system due to the effect of ovarian hormones. Understanding how gonadal hormone-MDMA interaction affects gender differences in the brain is essential to develop effective pharmacotherapy for both women and men. Finally, further investigation of the sex steroids involved in these effects appears to be necessary. As a library, NLM provides access to scientific literature. Funct Neurol. Find articles by Sara Soleimani Asl. Find articles by Mehdi Mehdizadeh. Find articles by Soudabeh Hamedi Shahraki. Find articles by Tayebeh Artimani. Find articles by Mohammad Taghi Joghataei. Collection date Apr-Jun. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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