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 preprint DOI: 10.64898/2026.06.28.734515 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study |
|---|---|
| Population | Mice engineered to express mGluR2-mCherry and 5-HT2A-eGFP-CT tagged receptors |
| Intervention | mGluR2 agonist pretreatment |
| Topics | Serotonin |
| Keywords | Metabotropic glutamate receptor Autoreceptor Metabotropic receptor Agonist In vivo Biophysics In vitro Cell biology Colocalization Pharmacology G protein-coupled receptor Microdialysis |
| Key points | No evidence for mGluR2 and 5-HT2A receptor colocalization or oligomerization was found, supporting a model where mGluR2 signaling modulates 5-HT2A activity via presynaptic inhibition of glutamate release rather than through direct heterodimer interactions. |
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |