Science Translational Medicine
December 11, 2019
Boris D. Heifets, Juliana S. Salgado, Madison Taylor et al.
119 citations
MDMA's prosocial effects can be separated from its addictive properties by using fenfluramine, a selective serotonin-releasing compound. This finding reveals a conserved neuronal pathway that could be targeted to develop new therapeutics with limited abuse liability, offering a potential strategy for creating safer treatments that promote social connection without the risks of addiction.
bioRxiv (Cold Spring Harbor Laboratory)
September 26, 2023
Yi-Ting Chiu, Wei Wang, Pierre Llorach et al.
15 citations
preprint
Psychedelic drugs such as LSD and psilocybin show promise as treatments for depression, anxiety, PTSD, migraine, and cluster headaches by activating the 5-HT2A receptor (HTR2A). Researchers engineered several new mouse lines to study the role of HTR2A and the neurons that express it. One line allows visualization of the receptor and identification of HTR2A-containing cells, providing a detailed anatomical map. Another line has a humanized version of the receptor, and a third enables targeted genetic manipulation. The mice exhibited expected behavioral responses to psychedelics, confirming their usefulness. Electrophysiology showed that serotonin increases firing of specific pyramidal neurons through HTR2A, consistent with the receptor's location on the cell surface. These tools will help clarify how psychedelics work at molecular, cellular, and behavioral levels.
bioRxiv (Cold Spring Harbor Laboratory)
June 30, 2026
Blake A Fordyce, Yi-Ting Chiu, Nicholas A. Wright et al.
Activation of mGluR2, the primary presynaptic autoreceptor for glutamate in the brain, attenuates the behavioral and electrophysiological effects of psychedelics. The mechanisms behind this are debated, with two competing hypotheses: direct actions via mGluR2/5-HT2A heterodimers, or presynaptic inhibition of glutamate release. In mice expressing tagged receptors, mGluR2 agonist pretreatment reduced the head twitch response induced by the psychedelic DOI. Multiple orthogonal in vivo and in vitro approaches found no evidence for receptor colocalization or oligomerization under basal or agonist-exposed conditions, nor for mGluR2-mediated modulation of 5-HT2A ligand binding. The findings support models where mGluR2 signaling modulates 5-HT2A receptor activity in layer V pyramidal neurons rather than requiring mGluR2/5-HT2A multimers.