Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

MDMA, an amphetamine analogue, primarily stimulates serotonin release with smaller increases in synaptic dopamine. The ratio of dopamine to serotonin increase predicts abuse liability, with higher ratios indicating greater risk. Despite a lower ratio, MDMA is misused. Repeated exposure produces neuroadaptive changes in both serotonin and dopamine systems, explaining the development and maintenance of self-administration in animals and substance use disorder in humans. Research shows serotonin inhibits the acquisition of MDMA self-administration, while dopamine is critical for its maintenance. The paper describes circuitry and serotonin receptors that modulate dopamine activity and reviews limited research on MDMA's effects on these receptor mechanisms.

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Abstract

Abstract Methylenedioxymethamphetamine (MDMA) is an amphetamine analogue that preferentially stimulates the release of serotonin (5HT) and results in relatively small increases in synaptic dopamine (DA). The ratio of drug‐stimulated increases in synaptic DA, relative to 5HT, predicts the abuse liability; drugs with higher DA:5HT ratios are more likely to be abused. Nonetheless, MDMA is a drug that is misused. Clinical and preclinical studies have suggested that repeated MDMA exposure produces neuroadaptive responses in both 5HT and DA neurotransmission that might explain the development and maintenance of MDMA self‐administration in some laboratory animals and the development of a substance use disorder in some humans. In this paper, we describe the research that has demonstrated an inhibitory effect of 5HT on the acquisition of MDMA self‐administration and the critical role of DA in the maintenance of MDMA self‐administration in laboratory animals. We then describe the circuitry and 5HT receptors that are positioned to modulate DA activity and review the limited research on the effects of MDMA exposure on these receptor mechanisms. image