Rationale: Although many studies have focused on the mechanisms underlying MDMA-induced neurotoxicity, little is known about the subsequent long-term response to psychostimulants following exposure to a neurotoxic dose of MDMA.

Objectives: We investigated the effect of pre-exposure to neurotoxic and non-neurotoxic doses of MDMA on the response of mice to the psychomotor stimulating effects of MDMA and cocaine.

Methods: To investigate MDMA-induced neurotoxicity, male Swiss Webster mice were subjected to three regimens of MDMA: i) 40 mg/kg x 2, ii) 30 mg/kg x 2, and iii) 15 mg/kg x 2 for 2 days. On day 5 following the last exposure to MDMA, the levels of dopaminergic and serotonergic markers were determined. For the behavioral experiments, mice received either a single injection of 10 mg/kg MDMA [MDMA(L)] or one of the following doses of MDMA: 30 mg/kg x 2 or 15 mg/kg x 2 for 2 days [MDMA (H)]. A third group received saline as a control. On day 5 after the last pretreatment injection, the first MDMA (10 mg/kg) challenge was given, and on day 12, cocaine (20 mg/kg) was administered. Subsequently, mice were re-challenged with MDMA on days 35, 50 and 80, after which locomotor activity was monitored by infrared beam-interrupts. On day 83, mice were killed to detect the levels of dopaminergic and serotonergic markers.

Results: MDMA-induced mortality and depletion of dopaminergic and serotonergic markers were dose-dependent. MDMA (H) mice endured a sensitized response to MDMA challenge from days 5 through 80, e.g. a persistent 3-fold increase in locomotor activity compared to the response of mice that were not pretreated with a neurotoxic dose of MDMA. The depletion of DAT and 5-HTT binding sites was sustained throughout this time period (64-68% of control). The MDMA (L) mice showed a sensitized response to MDMA only on day 5. Both MDMA (L) and MDMA (H) mice were sensitized to the cocaine challenge.

Conclusions: The induction of sensitization to the locomotor stimulating effects of MDMA and cocaine was independent of MDMA-induced neurotoxicity. However, the long-lasting maintenance of the sensitized response to MDMA may be related to the enduring neurotoxicity caused by MDMA.