A genetic deletion of the serotonin transporter differentially influences the behavioural effects of MDMA

Abstract

Background: While (±)-3,4-methylenedioxymethamphetamine (MDMA) primarily induces serotonin release, it also affects dopamine and noradrenaline transmission. It is, however, unclear what role each of these neurotransmitters play in the behavioural profile of MDMA. Methods: In this study we used the drug discrimination (DD) and the acoustic startle (ASR) paradigms to examine the behaviour of rats with and without a genetic deletion of the serotonin transporter SERT (SERT−/− and SERT+/+ rats). In DD, rats were trained to respond on different levers following an injection of 1.5 mg/kg MDMA, or saline. After acquisition, they were given a challenge dose of 0.5 mg/kg amphetamine (AMPH). In the ASR paradigm, SERT+/+ and SERT−/− rats were given 0, 5 or 10 mg/kg MDMA. Results: In DD, significantly fewer SERT−/− rats acquired MDMA discrimination. When the acquirers were challenged with AMPH, SERT+/+ showed partial, while SERT−/− rats showed full generalisation to MDMA. In the ASR paradigm, MDMA significantly reduced prepulse inhibition and startle habituation in SERT+/+ rats, while having no effect in SERT−/− rats. Conclusion: Together these data suggest that in wildtype rats the interoceptive cues of MDMA are primarily mediated by serotonin and to a lesser extent by dopamine and noradrenaline, while the effects in the startle paradigm are almost exclusively mediated via serotonin. Together, these data contribute to our understanding of the complex pharmacodynamics of MDMA.