Contribution of Impulsivity and Serotonin Receptor Neuroadaptations to the Development of an MDMA (‘Ecstasy’) Substance Use Disorder

Abstract

As is the case with other drugs of abuse, a proportion of ecstasy users develop symptoms consistent with a substance use disorder (SUD). In this paper, we propose that the pharmacology of MDMA, the primary psychoactive component of ecstasy tablets, changes markedly with repeated exposure and that neuroadaptations in dopamine and serotonin brain systems underlie the shift from MDMA use to MDMA misuse in susceptible subjects. Data from both the human and laboratory animal literature are synthesized to support the idea that (1) MDMA becomes a less efficacious serotonin releaser and a more efficacious dopamine releaser with the development of behaviour consistent with an SUD and (2) that upregulated serotonin receptor mechanisms contribute to the development of the MDMA SUD via dysregulated inhibitory control associated with the trait of impulsivity.

The neurobiology of impulsivity and substance use disorders: implications for treatment

“…Selective 5‐HT receptor agonists and antagonists have demonstrated elevated and blocked impulsiveness, respectively . Moreover, both human and animal trials have demonstrated that upregulated 5‐HT receptor mechanisms contribute to the development of SUDs via dysregulated IC associated with impulsivity …”

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

“…Our group has provided latencies to acquisition and percentage of rats that acquired self-administration of MDMA by adopting criteria based on responding derived from a control group that received placebo infusions dependent on a lever response as well as preference for an active lever that delivered drug infusions compared to an inactive lever that had no programmed consequences (Bird & Schenk, 2013;Bradbury et al, 2014;Schenk & Aronsen, 2017). Our findings from drug-naïve rats without any prior training to lever press support the idea that about 50% of the rats reliably self-administer MDMA within a 25-day period of 2-hr daily self-administration sessions or 10 days of 6-hr sessions, also found by another laboratory (Frankowska et al, 2019).…”