Neurochemical Substrates of MDMA Reward: Effects of the Inhibition of Serotonin Reuptake on the Acquisition and Reinstatement of MDMA-induced CPP

Abstract

Different neurotransmitter brain systems have been implicated in the rewarding effects of 3,4-methylenedioxymetamphetamine (MDMA), including dopamine or serotonin. Serotonin selective reuptake inhibitors (SSRI) are a commonly prescribed therapy for psychiatric disorders, and the SSRI fluoxetine is recommended for MDMA users due to its neuroprotective effect against MDMAinduced neurotoxicity. In the present work, we employed the conditioned place preference (CPP) paradigm to study how the inhibition of serotonin reuptake with fluoxetine affected the rewarding and reinstating effects of MDMA in adolescent male mice. Firstly, we evaluated the motivational effects of fluoxetine (1 and 10 mg/kg), administered alone or with a sub-threshold dose of MDMA (1.25 mg/kg). In a second experiment we evaluated the effects of a pretreatment with fluoxetine (1 and 10 mg/kg) on the subsequent acquisition of a CPP induced by MDMA (1.25 mg/kg). The effects of a priming dose of fluoxetine (1 and 10 mg/kg), MDMA (5 or 1.25 mg/kg) or both drugs together on the reinstatement of a previously extinguished CPP induced by MDMA (10 mg/kg) were studied in a third experiment. Fluoxetine did not induce motivational effects but did increase the rewarding effects of a sub-threshold dose of MDMA, and pretreatment with the high dose of fluoxetine had the same effect. Fluoxetine did not induce cross-reinstatement of the MDMA CPP, but the combination of an ineffective priming dose of MDMA and the highest dose of fluoxetine did induce reinstatement of CPP. Neurochemical experiments demonstrated alterations in monoamine levels of MDMA treated mice produced by fluoxetine. As a whole, these results show that the inhibition of serotonin reuptake potentiates the acquisition and reinstatement of MDMA-induced CPP and supports a role for serotonin in MDMA-induced reward.