5-HT 2C receptors in the nucleus accumbens constrain the rewarding effects of MDMA.

Autor: Pomrenze MB; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305., Vaillancourt S; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305., Salgado JS; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305., Raymond KB; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305., Llorach P; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305., Touponse GC; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305., Cardozo Pinto DF; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305., Rastegar Z; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305., Casey AB; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305., Eshel N; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305., Malenka RC; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305., Heifets BD; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305.; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 22. Date of Electronic Publication: 2024 Oct 22.
DOI: 10.1101/2024.10.20.619256
Abstrakt: 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-HT 1B R 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-HT 2C R antagonist (SB242084), but not by the 5-HT 1B R 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.
Competing Interests: CONFLICT OF INTERESTS B.D.H. is on the scientific advisory boards of Journey Clinical and Osmind, and is a paid consultant to Arcadia Medicine, Inc. N.E. is a paid consultant for Boehringer Ingelheim. R.C.M. is now on leave from Stanford, functioning as Chief Scientific Officer at Bayshore Global Management. R.C.M. is on the scientific advisory boards of MapLight Therapeutics, Bright Minds, MindMed, and Aelis Farma.
Databáze: MEDLINE
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