The effects of presence, versus absence, of estrogen on degree of (+)-MDMA-induced hyperactivity after 1, 2 or 4 mg/kg, was examined in female rats. (Rats were housed 4 per cage, but tested singly during the experimental session). The researchers first ovarectomized all rats, and then gave half 17Beta-estradiol (E2) implants that released approximately 40-50 pg/ml ET, considered a peak level of E2 normally achieved during rat proestrous (prior to and near ovulation). Three weeks after ovarectomy and after two 3-hour habituation sessions (one per day), rats were challenged with (+)-MDMA (1, 2 or 4 mg/kg) or cocaine (5, 10 or 20 mg/kg), and degree of activity was measured both via photobeam detection and by manual coding of videotape. Photobeam measures lasted for 60 minutes, but behavioral observation lasted 120 minutes. Ovarectomized rats receiving E2 supplements were more active than rats not receiving any E2 supplements. This difference was also seen in response to the highest dose of (+)-MDMA (4 mg/kg) and after cocaine as well, with E2-treated rats displaying more horizontal and vertical (e.g. rearing) activity than controls after drug challenge. Behavioral observation did not find any significant differences in MDMA-induced changes in non-locomotor activity (such as inactive sniffing, rearing) between rats with and without the E2 implants, so it appears that E2 levels specifically increased locomotor activity after (+)-MDMA. The authors noted that hyperactivity appeared almost immediately after cocaine injection (5 min post-drug), whereas hyperactivity after (+)-MDMA appeared 20 to 40 minutes post-drug. The researchers conclude that estrogen levels can alter response to psychostimulants. They propose that the differences in time course for cocaine and (+)-MDMA relate to pharmacokinetics and to the time course of dopamine release, with (+)-MDMA releasing dopamine later than cocaine. Since rats experienced peak E2 levels throughout the study, it remains unclear whether the same effects would occur with fluctuating estrogen levels, as those seen during a normal estrous cycle. Doses used in this study were deliberately chosen for their low probability of producing neurotoxicity, but no histological examinations were reported after study completion, and actual absence of neurotoxic effects cannot be stated. It should be remembered that humans ingest the racemate (±) MDMA) rather than one enantiomer alone, and that recent studies in mice (Fantegrossi et al. 2003) found that the racemate differed from either MDMA enantiomer on its effects on locomotion.