Snapshot IP 1 Detection Following 5-HT 2 A Receptor Stimulation in the Mouse Brain
Mario de la Fuente Revenga, Javier González-Maeso
ACS Chemical Neuroscience January 2, 2026 DOI: 10.1021/acschemneuro.5c00932 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mouse brain tissue (frontal cortex, striatum, cerebellum) |
| Interventions | DOI LSD lisuride MDMA 5-hydroxytryptophan fluoxetine |
| Topics | Serotonin |
| Citations | 1 |
| Key findings | The ex vivo platform measuring IP1 turnover in mouse frontal cortex distinguishes psychedelic from nonpsychedelic 5-HT2AR agonists, with DOI and LSD increasing IP1 but lisuride not, and MDMA increasing IP1 via serotonin release. |
Abstract
The distinct subjective effects that define psychedelics such as lysergic acid diethylamide (LSD), psilocybin, or 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) as drug class are causally linked to the activation of the serotonin 2A receptor (5-HT 2A R). However, some aspects of 5-HT 2A R pharmacology remain elusive, such as what molecular drivers differentiate psychedelic from nonpsychedelic 5-HT 2A R agonists. We developed an ex vivo platform to obtain snapshots of drug-mediated 5-HT 2A R engagement of the canonical G q/11 pathway in native tissue. This nonradioactive methodology captures the pharmacokinetic and pharmacodynamic events leading up to changes in inositol monophosphate (IP 1 ) in the mouse brain. The specificity of this method was assessed in homogenates from the frontal cortex in DOI-treated wild-type and 5-HT 2A R knockout (5-HT 2A R-KO) animals compared to other brain regions, namely, striatum and cerebellum. The effect of DOI on mouse frontal cortex IP 1 was time-bound, dose-dependent, and was correlated to head twitch response counts. We observed that IP 1 levels in frontal cortex homogenates from mice treated with LSD and lisuride varying in magnitude, consistent with LSD’s 5-HT 2A R agonism and psychedelic nature and lisuride’s lack thereof. 3,4-Methylenedioxymethamphetamine (MDMA) evoked an increase in the IP 1 signal in the frontal cortex that was not matched by the serotonin precursor 5-hydroxytryptophan or the serotonin reuptake inhibitor fluoxetine. We attribute the differences in the readout primarily to the indirect stimulation of 5-HT 2A R by MDMA via the release of serotonin from its presynaptic terminals. This methodology enables one to capture a snapshot of IP 1 turnover in the mouse brain that can provide mechanistic insights into the study of psychedelics and G q/11 -coupled receptors.
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 |
Citations in the library
Cites 26
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Psychometric Evaluation of the Altered States of Consciousness Rating Scale (OAV) PLoS One August 31, 2010
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proceedings of the National Academy of Sciences March 1, 1992
- Activation of Serotonin 2A Receptors Underlies the Psilocybin-Induced Effects on Oscillations, N170 Visual-Evoked Potentials, and Visual Hallucinations Journal of Neuroscience June 19, 2013
and 21 more in the library