PRECLINICAL STUDY: Atypical development of behavioural sensitization to 3,4‐methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) in adolescent rats and its expression in adulthood: role of the MDMA chirality

Repeated treatment of adolescent rats with the drug MDMA (Ecstasy) or its S-enantiomer caused immediate massive hyperactivity and, after a short habituation period, led to behavioral sensitization—a heightened response to the drug over time. The R-enantiomer did not cause hyperactivity and even reduced movement with repeated doses, but when given together with the S-enantiomer it increased hyperactivity and made the sensitization state-dependent. Rats pretreated with R-MDMA showed a sensitized response in adulthood when later given the racemic mixture. These results indicate that even without substantial neurotoxicity, both MDMA enantiomers can cause long-term changes in brain circuitry and behavior when given repeatedly during adolescence.

Study at a glance

Abstract

ABSTRACTDespite the great popularity of 3,4‐methylenedioxymethamphetamine (MDMA, Ecstasy) as a drug of abuse, not much is known about the detailed mechanisms of the acute and subchronic effects of the drug. There is especially a lack of information about the distinct behavioural effects of its optical isomers (enantiomers) R‐ and S‐MDMA compared with the racemic RS‐MDMA. For this purpose, adolescent rats were repetitively treated during two treatment stages (stage 1: days 1–10; stage 2: days 15, 17, 19) with RS‐MDMA (5 or 10 mg/kg) or each of the respective enantiomers (5 mg/kg). The repeated treatment started on postnatal day (PND) 32 and locomotor activity was measured on each day by means of a photobeam‐equipped activity box system. RS‐MDMA or S‐MDMA administration led acutely to massive hyperlocomotion and subchronically, to the development of behavioural sensitization after a short habituation period. R‐MDMA was free of hyperactivating effects and even decreased locomotor behaviour upon repeated treatment. Nevertheless, co‐administration of R‐MDMA increased the hyperactivity of S‐MDMA and made the S‐MDMA induced behavioural sensitization state‐dependent. The animals pre‐treated with R‐MDMA showed a sensitized response in adulthood when tested with RS‐MDMA. Our results indicated that even in the absence of substantial neurotoxicity, both MDMA enantiomers can lead to long‐term changes in brain circuitry and concomitant behavioural changes when repeatedly administered in adolescence. The sensitization development was most pronounced in the animals treated with S‐ and RS‐MDMA; the animals with R‐MDMA did not develop sensitization under repeated treatment but expressed a sensitized response when challenged with RS‐MDMA.