Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

Abstract

Rationale 3,4-Methylenedioxymethamphetamine (MDMA; "Ecstasy") use has been associated with acute toxicities and persistent depletion of the neurotransmitter serotonin (5-HT). Objectives This study investigates whether sex differences in the acute and long-term effects of MDMA exist. Methods Male and female rats received saline or 15 mg/kg MDMA, ip, bid for 4 days. Temperature was monitored on days 1 and 4. Locomotor activity was measured in a second cohort of animals on days 1 and 4 and after recovery on day 14. The effects of MDMA on performance in a plus maze task and brain levels of serotonin (5-HT) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in a third cohort of animals 2 weeks after the last MDMA treatment. Results Locomotor activity and temperature increased after MDMA administration on day 1. The drug-induced increases in temperature but not locomotion attenuated with repeated MDMA administration. Male and female MDMA-treated rats spent less time in the open arms of the elevated plus maze and had less 5-HT and 5-HIAA in all brain regions 2 weeks after the end of treatment. Temperature effects of MDMA and persistent effects on plus maze and brain serotonin content were similar in males and females. In contrast, females exhibited markedly greater locomotor stimulation after acute MDMA and also showed sensitization to an acute challenge 2 weeks later. Conclusions MDMA elicits substantially greater locomotor activation in female rats than in males, but persistent effects on anxiety and serotonin content were similar in males and females.

Sex differences in MDMA-induced toxicity in Sprague-Dawley rats

“…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 (2007) showed that MDMA elicits substantially greater locomotor activation in female rats than in male rats. 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, 2001), and more pronounced depression following ecstasy use in women (Verheyden et al, 2002).…”

Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview

“…Females exhibited markedly greater locomotor stimulation after acute MDMA and also showed sensitization to an acute challenge, 2 weeks later. MDMA elicits substantially greater locomotor activation in female rats than in males, but persistent effects on anxiety and 5-HT content were found to be similar in males and females [152].…”

“…However, in 1985, 1 year before the first report on MDMA-induced neurotoxicity, another study had reported that MDA, a major metabolite of MDMA and also a hallucinogenic drug of abuse, was neurotoxic to rat serotonergic neurons [244]. After these early reports, many others continued to prove both biochemically and histologically, using state-of-the-art techniques, that MDMA produces neurotoxicity to serotonergic terminals and also to other neurons of rats [142,152,166,.…”

“…MDMA was shown to cause acute dose-dependent hyperthermia in many laboratory animals, namely, in mice [51,[133][134][135][136][137][138][139][140][141], rats [142][143][144][145][146][147][148][149][150][151][152][153][154][155][156], in rabbits [157,158], guinea pigs [159], and pigs [160]. In unrestrained non-human primates, MDMA was also shown to dose-dependently increase body temperature, leading to hyperthermia [161][162][163][164].…”

“…This phenomenon has been considered, for many years, a useful animal model for the development of psychosis [208]. As for Amph, MDMA was also was shown to elicit long-term behavioral and neurochemical sensitization in rats after repeated exposure [152,178,[208][209][210]. In male SpragueDawley rats, locomotor activity in response to MDMA at three doses (2.5, 5.0, 7.5 mg/kg, i.p.)…”