No evidence for direct physical interaction of 5-HT 2A -mGluR2 receptors in vitro or in vivo
Blake A Fordyce, Yi-Ting Chiu, Nicholas A. Wright, Kensuke Sakamoto, Scott P. Lyons, Thomas S. Webb, Hayleigh E Tilton, Jessica J. Walsh, Gerard J. Marek, Vincent Setola, Bryan L. Roth
bioRxiv (Cold Spring Harbor Laboratory) June 30, 2026 Peer reviewed DOI: 10.64898/2026.06.28.734515 via OpenAlex
Summary
Activation of mGluR2, a presynaptic autoreceptor for glutamate, reduces the effects of psychedelics like DOI in mice. The study found no evidence that mGluR2 interacts directly with 5-HT 2A receptors, either through colocalization or modulation of ligand binding. Instead, it suggests that mGluR2 signaling influences the activity of 5-HT 2A receptors in pyramidal neurons without requiring receptor multimers.
Study at a glance
| Design | experimental study |
|---|---|
| Population | mice engineered to express specific receptor tags |
| Key finding | mGluR2 agonist pretreatment attenuates the head twitch response induced by the psychedelic drug DOI. |
Abstract
Abstract Activation of mGluR2 (metabotropic glutamate receptor 2), the primary presynaptic autoreceptor for glutamate in the brain, is well established to attenuate the psychedelics-mediated behavioral and electrophysiological effects. However, the mechanisms responsible for these actions are controversial. The two competing mechanistic hypotheses have been proposed to explain this phenomenon are: (1) direct actions mediated by mGluR2/5-HT 2A heterodimers, and (2) inhibition of 5-HT 2A -mediated excitation of pyramidal neurons via presynaptic inhibition of glutamate release by mGluR2 receptors. Consistent with prior reports, we show that mGluR2 agonist pretreatment attenuates the head twitch response induced by the psychedelic drug 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice engineered to express mGluR2-mCherry and 5-HT 2A -eGFP-CT tagged receptors. We next employed multiple orthogonal in vivo and in vitro approaches to explore the potential for direct physical interactions between mGluR2 and 5-HT 2A receptors. Across all approaches, we found no evidence for receptor colocalization or oligomerization under basal or 5-HT 2A agonist-exposed conditions in vitro or in vivo . Radioligand binding and kinetic analyses revealed no evidence for mGluR2-mediated modulation of 5-HT 2A ligand binding in vitro or in vivo . Collectively, our findings support models in which mGluR2 signaling modulates the activity of Gα q -coupled 5-HT 2A receptors in layer V pyramidal neurons, rather than models positing the requirement of mGluR2/5-HT 2A multimers.