This study examined the role played by dentate (gyrus) granule cells in modulating MDMA-induced increases in locomotion and signs of gene expression in rats. In this study, rats underwent dentate cell destruction, sham operation, or no operation, and then animals in each condition received saline, 2, 5 or 10 mg/kg MDMA. Locomotion was assessed by detecting motion with photobeam arrays during a 90-minute period, with rats placed in the test chamber 1 h pre-MDMA. Rats were killed immediately after assessing changes in locomotion, and Fos activation (gene associated with gene transcription, indicative of gene expression) was measured in selected brain areas; L and R medial prefrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, piriform cortex, dorsal striatum, nucleus accumbens core, and n. accumbens shell. Fos-reactive cells were detected via immunoassay and image analysis software. Lesioned rats were significantly more active after saline than intact animals, and more active than sham-lesioned rats given saline, though not significantly so. Intact, sham-lesioned and lesioned rats showed increased locomotion to 2, 5 and 10 mg/kg MDMA, but MDMA-induced locomotion was significantly higher in lesioned rats after all doses of MDMA than in intact or sham-lesioned rats. (The authors did not compare activity across doses, but MDMA-induced locomotion appears to be dose-dependent, especially in lesioned rats). MDMA dose-dependently increased Fos-reactive cells in all brain areas assessed in lesioned, sham-lesioned and intact rats. However, lesioned animals showed more Fos-reactive cells in the nucleus accumbens core than sham-lesioned or intact rats, with the comparison true for all treatments (saline, 2, 5 and 10 mg/kg MDMA). These findings suggest that absences of dentate granule cells increased locomotion in response to stress loading, perhaps due to the removal of an inhibitory system operating from the hippocampus (including dentate gyrus and CA regions) to the subiculum. MDMA does not specifically activate n. accumbens core, but lesioning dentate granule cells enhances activation, presumably through attenuation of or interference with an inhibitory loop. This study also suggests that MDMA alters gene expression in a number of cortical areas, including prefrontal and piriform cortex, striatum, and n. accumbens. The relevance of study findings to Ecstasy users is unclear, but suggests that individual differences in acute subjective or physiological MDMA effects might similarly relate to pre-existing differences in brain function, including brain function in areas not directly affected by MDMA.