The effects of neonatal MDMA exposure on subsequent spatial learning and memory in rats was examined by assessing performance in straight channel, sequential and platform based water maze tasks. Performance of rats given 2 daily doses of 20 mg/kg MDMA for 10 days (from postnatal (PN) days 11 to 20) was compared with that of saline-treated rats, either raised in small or large litters, and rats that were only weighed and not given saline injections. Large litters were formed by placing 8 additional pups into existing litters, starting on PN day 11, and keeping additional pups with litters at least up to PND 20. Analyses of body weight across group found that MDMA-treated and large-litter rats weighed less than saline-treated and weighed rats. Straight-channel swimming was assessed on PND50 (30 d post-regimen), and navigation of the Cincinnati Multiple-T Water Maze (CWM) was assessed on PND51. The CWM consists of nine joined T-mazes and an escape ramp placed at an exit; performance is measured via number of errors (entries into cul-de-sacs) and escape latency, or time elapsed between entry and escape. Acquisition of the Morris Water Maze (MWM, rat must locate and swim to hidden platform) began on PND57. MWM performance was assessed after shifting the platform to a novel position (PND 64), after a smaller platform was shifted back to the original position (PND 71), and after a cued platform (marker visible above platform (PND 78). Performance on the forced-swim test was observed on PND 91. Immediately after forced swim, one male and one female from each litter were killed, and cortisol and ACTH levels were assessed from trunk blood collected form these animals. While there were no between-group differences in straight-channel swimming, male MDMA-treated rats had longer escape latencies and committed more errors on the CWM than male rats in all other treatment groups. MDMA-treated rats did less well at platform location during MWM acquisition than saline-treated or weighed animals, and MDMA-treated rats were farther from platform location than saline-treated or weighed rats on probe trials (platform is removed). (There was a trend for MDMA-treated rats to do less well than large-litter rats in platform location ). MDMA-treated rats fared less well (longer path lengths, longer time spent finding the platform) than saline-treated or weighed controls on shifted-platform trials, and female MDMA-treated rats did less well than large-litter females. However, on probe trials, only large-litter rats were farther from the platform location than saline-treated or weighed rats. MDMA-treated rats took more time in platform location and had longer path lengths than saline-treated or weighed rats in trials with shifted, reduced-size platform, and there was a trend for longer escape latency in MDMA-treated rats than in large-litter rats. On memory (probe) trials, MDMA-treated animals were farther from platform location than rats in all other treatment conditions. All groups performed similarly in the cued-platform condition, though platform location was faster in males than females, and there were no between-group differences in cortisol or ACTH response to forced-swim stress. (Females had higher cortisol levels than males.) Study findings suggest neonatal exposure to MDMA affects spatial memory, and that gender-specific strategies may be differentially affected by developmental MDMA exposure, evident in impaired CWM performance in male MDMA-treated rats versus impaired MWM performance in female MDMA-treated rats. Despite the researchers' attempt to control for body weight, this variable may still play a role independent of or in addition to that of MDMA, as performance in large-litter rats was often not much better than that of MDMA-treated animals in many cases. It is important to note that the MDMA dose regimen used was extensive (dosing over 10 days), and that no histological examinations of brain serotonin were performed, though such a regimen is presumably neurotoxic. This paper is one of a growing number suggesting developmental effects of MDMA exposure (Broening et al. 2001; Meyer et al. 2002; Morley-Fletcher et al. 2002; Won et al. 2002), and it is the first to have attempted to control for effects arising from handling and body weight.