MDMA Enantiomers: an Exploration into 5-HT2AR Necessity in Non-Hallucinogen Induced Frontal Cortex Plasticity

Author

Maya C. Gaines-Smith, Virginia Commonwealth UniversityFollow

Author ORCID Identifier

https://orcid.org/0000-0001-8652-0194

Defense Date

2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Javier González-Maeso

Second Advisor

John Bigbee

Third Advisor

Peter Hamilton

Fourth Advisor

Dana Selley

Fifth Advisor

Jennifer Wolstenholme

Abstract

Entactogen 3,4-methylenedioxymethamphetamine (MDMA) has gained increasing attention as a potential psychotherapeutic, particularly for psychiatric disorders that have proven to be resistant to traditional treatments. Despite its growing popularity, the complete neurobiological mechanism of MDMA enantiomers, as well as the role of sex in these mechanisms, remains to be fully elucidated. Current ongoing research implicates agonism of the serotonin (5-HT) 2A receptor (5-HT_2AR) and neuroplastic growth in the success of other psychoactive and hallucinogenic pharmacotherapeutics, highlighting the importance of understanding the role that the 5-HT_2AR plays in the therapeutic mechanism of action of MDMA enantiomers. The culmination of this dissertation research combines in vivo, ex vivo, and in vitro methodologies to parse out the activity of S(+)-MDMA and R(-)-MDMA as it pertains to sex, the 5-HT_2AR, and dendritic spine density of frontal cortex (FC) pyramidal neurons. This work demonstrates that both racemic (+/-) and S(+)-MDMA exhibit partial agonism at the 5-HT_2AR as measured by in vitro intracellular calcium (Ca²⁺) signaling in HEK293 cells stably expressing the 5-HT_2AR, while R(-)-MDMA does not. In vivo, 5-HT_2AR agonism dependent head twitch response (HTR), was observed in a dose dependent manner following administration of both R(-)-MDMA and S(+)-MDMA via intraperitoneal (i.p.) injection of female mice, however only S(+)-MDMA induced HTR in male mice. Ex vivo, inositol monophosphate (IP₁), accumulation in the FC was quantified in both male and female mice, with only S(+)-MDMA inducing significant increase as compared to saline in both sexes. Interestingly, this effect was blocked with the IP administration of serotonin transporter (SERT) blocker fluoxetine one hour prior to administration of MDMA, indicating that the S(+)-MDMA induced IP₁ signal observed is a result of the SERT mediated influx of 5-HT. Conversely, IP₁ accumulation of selective 5-HT_2AR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) remained unaffected following pharmacological blockade of SERT with fluoxetine. Lastly, S(+)-MDMA was found to significantly increase dendritic spine density in both wild-type (WT) and 5-HT_2AR knockout (KO) C57BL/6J male mice, while female mice did not exhibit significant increase for either enantiomer in both WT and KO models. Cumulatively, this work highlights the stereoselectivity of MDMA enantiomers at the 5-HT_2AR, as well as further elucidates its sex specific neurobiological mechanism of action.

Rights

© Maya C. Gaines-Smith

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

10-13-2025