3,4‐Methylenedioxymethamphetamine (MDMA) does not induce robust psychomotor activation and 50‐kHz ultrasonic vocalisations in tryptophan hydroxylase 2 (Tph2) ‐deficient rats lacking serotonin in the central nervous system

Background and Purpose 3,4‐Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, is a psychostimulant with entactogenic properties and known to induce arousal and euphoria. As an amphetamine derivate, MDMA acts on the monoamine systems in the brain and stimulates release of dopamine (DA), noradrenaline (NA) and serotonin (5‐HT), yet their individual contributions in driving arousal and euphoria remain controversial. Experimental Approach We studied the effects of central 5‐HT deficiency and compared the behavioural responses evoked by MDMA (10 mg kg −1 ) in female and male Tph2 −/− knockout and Tph2 +/− heterozygous rats, with no or reduced central 5‐HT, respectively, to Tph2 +/+ wild‐type (WT) littermate controls. As markers for arousal and euphoria, we assessed psychomotor activation and 50‐kHz ultrasonic vocalisations (USV), respectively. Key Results Central 5‐HT deficiency caused by genetic ablation of Tph2 blocked MDMA‐induced psychomotor activation and 50‐kHz USV. Whereas MDMA evoked a substantial increase in psychomotor activation in Tph2 +/− heterozygous rats and Tph2 +/+ WT littermates, no such prominent response was seen in Tph2 −/− knockout rats. Moreover, MDMA evoked a mild increase in 50‐kHz USV in Tph2 +/+ WT littermates but not Tph2 +/− heterozygous and Tph2 −/− knockout rats. Genotype effects were robust and typically seen in both sexes. Conclusions and Implications MDMA does not induce a prominent increase in psychomotor activation and 50‐kHz USV in Tph2 ‐deficient rats lacking 5‐HT in the central nervous system. This suggests that the robust induction of arousal and euphoria by MDMA in intact rats is not driven by the release of DA or NA, but depends on central 5‐HT.