About half of rats fail to acquire MDMA self-administration, and the difference is not due to how the drug is metabolized. MDMA triggers greater release of serotonin than dopamine in the brain. Rats that did acquire self-administration showed lower serotonin overflow than those that did not. Destroying serotonin neurons with a toxin made more rats acquire MDMA self-administration and speeded acquisition of cocaine self-administration. These findings suggest that serotonin limits initial sensitivity to MDMA's rewarding effects and delays reliable self-administration.
MDMA's behavioral effects are primarily due to central nervous system actions, not peripheral ones. In rats trained to distinguish MDMA from saline, the drug produced dose-related increases in drug-appropriate responses. A quaternary analog of MDMA (qMDMA), which cannot cross the blood-brain barrier, did not substitute for MDMA when given peripherally, but partially substituted when infused directly into the brain. This validates qMDMA as a tool for separating central from peripheral effects of MDMA.