5-HT2C receptors in the nucleus accumbens constrain the rewarding effects of MDMA.
Matthew B Pomrenze, Sam Vaillancourt, Juliana S Salgado, Kendall Raymond, Pierre Llorach, Gavin C Touponse, Daniel F. Cardozo Pinto, Zahra Rastegar, Austen B Casey, Neir Eshel, Robert C. Malenka, Boris D. Heifets
bioRxiv : the preprint server for biology October 22, 2024 preprint DOI: 10.1101/2024.10.20.619256 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Mice |
| Interventions | MDMA methamphetamine (R)-MDMA escitalopram SB242084 NAS-181 |
| Dose | 7.5 and 15 mg/kg MDMA, 2 mg/kg methamphetamine |
| Topics | Addiction MDMA Serotonin |
| Keywords | Psychotherapy |
| Citations | 1 |
| Key findings | MDMA's serotonin release limits its dopamine release and abuse potential through actions in the nucleus accumbens, suggesting separate mechanisms for its prosocial and reinforcing effects. |
Abstract
MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT1BR activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of (R)-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo, increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT2CR antagonist (SB242084), but not by the 5-HT1BR antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, (R)-MDMA is predicted to have prosocial effects and low abuse potential.