MDMA (ecstasy) activates trace amine-1 receptors (TA1Rs), which normally inhibit dopamine and serotonin release. In mice lacking TA1Rs, MDMA caused only hyperthermia (not the biphasic temperature response seen in normal mice), produced larger increases in dopamine levels in the striatum, frontal cortex, and nucleus accumbens, and led to greater locomotion that was blocked by haloperidol. Serotonin release was also amplified in TA1R-deficient mice. A TA1R agonist reduced the dopamine- and serotonin-releasing effects of another drug in normal mice but not in knockout mice. TA1Rs thus limit MDMA's neurochemical and behavioral effects, suggesting they play a regulatory role in the drug's actions.
The designer drug mephedrone, compared with MDMA (ecstasy) and amphetamine in rats, rapidly increased dopamine levels in the nucleus accumbens by 496% and serotonin levels by 941%, closely matching MDMA's serotonin release but also producing an amphetamine-like fast dopamine surge and elimination. Amphetamine raised dopamine by 412% and serotonin by only 165%. Mephedrone's dopamine levels cleared within 25 minutes, versus 303 minutes for MDMA, suggesting its brief but potent effect on the brain's reward system may underlie strong addictive potential. Locomotor activity increased most with amphetamine; mephedrone and MDMA had weaker, shorter effects.