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<p>The psychoactive entactogen 3,4-methylenedioxymethamphetamine (MDMA), widely known as a recreational drug, is gaining renewed attention as a potential psychotherapeutic adjunct for treatment-resistant psychiatric disorders, yet its neurobiological mechanisms – particularly those related to its stereoisomers and sex-specific effects – remain poorly understood. Here, we report stereoselective and sex-dependent actions of MDMA on serotonin (or 5-hydroxytryptamine) 2A receptor (5-HT<sub>2A</sub>R)-mediated signaling and dendritic structural plasticity in mouse frontal cortex. Using both in vitro and in vivo approaches, we found that racemic MDMA and <i>S</i>(+)-MDMA exhibit weak partial agonism at 5-HT<sub>2A</sub>R in HEK293 cells, whereas <i>R</i>(–)-MDMA shows negligible functional activity despite higher specific binding affinity. In vivo, <i>S</i>(+)-MDMA elicited a dose-dependent head-twitch response (HTR) in both sexes, while <i>R</i>(–)-MDMA-induced HTR only in females. Correspondingly, <i>S</i>(+)-MDMA increased inositol monophosphate (IP<sub>1</sub>) accumulation in the frontal cortex of male and female mice, whereas <i>R</i>(–)-MDMA showed minimal effects. Structurally, <i>S</i>(+)-MDMA enhanced dendritic spine density in male frontal cortex in a partially 5-HT<sub>2A</sub>R-dependent manner, while no spine remodeling was observed in females or with <i>R</i>(–)-MDMA. Pharmacological blockade of the serotonin transporter (SERT) with fluoxetine fully prevented <i>S</i>(+)-MDMA-induced HTR and IP<sub>1</sub> signaling, without affecting responses to the direct 5-HT<sub>2A</sub>R agonist DOI. These findings indicate that MDMA engages 5-HT<sub>2A</sub>R signaling indirectly via serotonin efflux and that this effect is both stereoselective and sex-dependent in mice, uncovering a previously unrecognized interaction between sex, MDMA stereochemistry, and 5-HT<sub>2A</sub>R-mediated cortical plasticity, with important implications for the rational design of MDMA-based therapeutics.</p>

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Stereoselective, sex-dependent 5-HT2A receptor modulation of cortical plasticity by MDMA in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月2日

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  • Maya C. Gaines-Smith,
  • Justin M. Silverman,
  • Michael Fiorillo,
  • Jason Younkin,
  • Karah N. Moore,
  • Jessica L. Maltman,
  • Mario de la Fuente Revenga,
  • Jennifer T. Wolstenholme,
  • Richard A. Glennon,
  • Małgorzata Dukat,
  • Javier González-Maeso

摘要

The psychoactive entactogen 3,4-methylenedioxymethamphetamine (MDMA), widely known as a recreational drug, is gaining renewed attention as a potential psychotherapeutic adjunct for treatment-resistant psychiatric disorders, yet its neurobiological mechanisms – particularly those related to its stereoisomers and sex-specific effects – remain poorly understood. Here, we report stereoselective and sex-dependent actions of MDMA on serotonin (or 5-hydroxytryptamine) 2A receptor (5-HT2AR)-mediated signaling and dendritic structural plasticity in mouse frontal cortex. Using both in vitro and in vivo approaches, we found that racemic MDMA and S(+)-MDMA exhibit weak partial agonism at 5-HT2AR in HEK293 cells, whereas R(–)-MDMA shows negligible functional activity despite higher specific binding affinity. In vivo, S(+)-MDMA elicited a dose-dependent head-twitch response (HTR) in both sexes, while R(–)-MDMA-induced HTR only in females. Correspondingly, S(+)-MDMA increased inositol monophosphate (IP1) accumulation in the frontal cortex of male and female mice, whereas R(–)-MDMA showed minimal effects. Structurally, S(+)-MDMA enhanced dendritic spine density in male frontal cortex in a partially 5-HT2AR-dependent manner, while no spine remodeling was observed in females or with R(–)-MDMA. Pharmacological blockade of the serotonin transporter (SERT) with fluoxetine fully prevented S(+)-MDMA-induced HTR and IP1 signaling, without affecting responses to the direct 5-HT2AR agonist DOI. These findings indicate that MDMA engages 5-HT2AR signaling indirectly via serotonin efflux and that this effect is both stereoselective and sex-dependent in mice, uncovering a previously unrecognized interaction between sex, MDMA stereochemistry, and 5-HT2AR-mediated cortical plasticity, with important implications for the rational design of MDMA-based therapeutics.