Opposite effects of 3,4-methylenedioxymethamphetamine (MDMA) on sensorimotor gating in rats versus healthy humans

Rationale: Prepulse inhibition of acoustic startle refers to the reduction in the startle response when the startling stimulus is preceded by a weak p repulse stimulus. This phenomenon provides an operational measure of sensor imotor gating that has been found to be reduced in patients with schizophre nia and rats treated with serotonin agonists or serotonin releasers. Object ive: In this study, we compared the effects of a serotonin releaser, MDMA, on prepulse inhibition in laboratory rats and healthy human volunteers. In particular, we investigated whether MDMA disrupts PPI in humans as observed in animal studies. Methods: Rats were tested after placebo and MDMA in a c ounterbalanced order at an interval of 1 week, with separate groups of rats being used for each dose of MDMA (1.7, 5.4 and 17.0 mg/kg). On each test d ay, rats were first tested after no injections and retested 2 h later, 10 m in after a subcutaneous injection of placebo or MDMA. For the human study, a placebo-controlled within-subject design and double-blind procedures were used. Subjects were examined twice at a 2 to 4 week interval after either placebo or drug administration (order being counterbalanced). On each test day, subjects underwent baseline testing including psychological and PPI me asures. Ninety minutes later, subjects received placebo or MDMA (1.7 mg/kg PO) and were retested after 75 min during the peak of behavioral effects of MDMA. Results. As expected, MDMA decreased prepulse inhibition in a dose-r elated fashion in rats. In contrast, a typical recreational dose of MDMA (1 .7 mg/kg, orally) increased prepulse inhibition in subjects experiencing ro bust psychological effects. Conclusions: This surprising disparity between the effects of the drug in rats and humans may reflect a species-specific d ifference in the mechanism of action of MDMA or in the behavioral expressio n of a similar pharmacological effect, or both.