3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA) DOES NOT INDUCE ROBUST PSYCHOMOTOR AND 50-KHZ ULTRASONIC VOCAL RESPONSES IN <EM>TPH2</EM>-DEFICIENT RATS WITHOUT SEROTONIN IN THE CENTRAL NERVOUS SYSTEM

3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, is a psychostimulant with entactogenic properties and known to induce arousal and euphoria. As 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. We studied the effects of central 5-HT deficiency on MDMA-induced arousal and euphoria using a 5-HT-deficient animal model lacking tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme for 5-HT synthesis in central nervous system. The behavioral responses evoked by MDMA (10 mg/kg) in female and male Tph2^−/− knockout and Tph2^+/− heterozygous rats, i.e., with no or reduced central 5-HT, respectively, were compared to Tph2^+/+ wildtype littermate controls. As markers for arousal and euphoria, we assessed psychomotor activation and 50-kHz-ultrasonic vocalizations (USV), respectively. We show that while MDMA evoked a substantial increase in psychomotor activation in Tph2^+/− heterozygous rats and Tph2^+/+ wildtype littermates, no such prominent response was seen in Tph2^−/− knockout rats. Moreover, MDMA evoked a mild increase in 50-kHz-USV in Tph2^+/+ wildtype littermates but not Tph2^+/− heterozygous and Tph2^−/− knockout rats. Genotype effects were robust and typically seen in both sexes. Together, 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.