Serotonin 2C receptors are also important in head-twitch responses in male mice.
Raly James Perez Custodio, Darlene Mae Ortiz, Hyun Jun Lee, Leandro Val Sayson, Mikyung Kim, Yong Sup Lee, Kyeong-Man Kim, Jae Hoon Cheong, Hee Jin Kim
Psychopharmacology July 1, 2025 DOI: 10.1007/s00213-023-06482-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male mice |
| Interventions | Methallylescaline (MAL) 4-Methyl-2 5 β-trimethoxyphenethylamine (BOD) |
| Dose | 1 mg/kg and 30 mg/kg |
| Measures | head-twitch response (HTR) |
| Topics | Mescaline Serotonin |
| Keywords | Bod Head-twitch response Inflammation Mal Novel psychoactive substances Phenethylamines |
| Citations | 8 |
| Key findings | Activation of 5-HT2C receptors, alone or with 5-HT2A receptors, induces head-twitch responses in male mice, and high doses of MAL and BOD produce neurotoxic effects with pro-inflammatory cytokine activation. |
Abstract
Serotonergic psychedelics exert their effects via their high affinity for serotonin (5-HT) receptors, particularly through activating 5-HT2A receptors (5-HT2AR), employing the frontal cortex-dependent head-twitch response (HTR). Although universally believed to be so, studies have not yet fully ascertained whether 5-HT2AR activation is the sole initiator of these psychedelic effects. This is because not all 5-HT2AR agonists exhibit similar pharmacologic properties. This study aims to identify and discriminate the roles of 5-HT2AR and 5-HT2CR in the HTR induced by Methallylescaline (MAL) and 4-Methyl-2,5,β-trimethoxyphenethylamine (BOD) in male mice. Also, an analysis of their potential neurotoxic properties was evaluated. Male mice treated with MAL and BOD were evaluated in different behavioral paradigms targeting HTR and neurotoxicity effects. Drug affinity, pharmacological blocking, and molecular analysis were also conducted to support the behavioral findings. The HTR induced by DOI has been extensively characterized in male mice, making it a good positive control for this study, specifically for comparing the pharmacological effects of our test compounds. The activation of 5-HT2CR, alone or in concert with 5-HT2AR, produces a comparable degree of HTRs (at a dose of 1 mg·kg-1), with divergent 5-HT2CR- and 5-HT2AR-Gqα11-mediated signaling and enhanced neurotoxic properties (at a dose of 30 mg·kg-1) coupled with activated pro-inflammatory cytokines. These findings show these compounds' potential psychedelic and neurotoxic effects in male mice. These findings showed that while 5-HT2AR is the main initiator of HTR, the 5-HT2CR also has a distinct property that renders it effective in inducing HTR in male mice.
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
Cited by 8
- 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review. ACS Pharmacology & Translational Science June 14, 2024
- The immunomodulatory effects of classical psychedelics: A systematic review of preclinical studies Progress in Neuro-Psychopharmacology and Biological Psychiatry September 7, 2024
- Narrating the psychoneuroimmunomodulatory properties of serotonin 5-HT2A receptor psychedelics from a transdiagnostic perspective. Acta Neuropsychiatrica July 25, 2025
- High dose of psilocybin induces acute behavioral changes without inducing conditioned place preference in Sprague-Dawley rats Journal of Psychopharmacology September 22, 2025
- The 4-alkyl chain length of 2,5-dimethoxyamphetamines differentially affects in vitro serotonin receptor actions versus in vivo psychedelic-like effects Molecular Psychiatry November 5, 2025
and 3 more in the library
Cites 58
- Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings The Lancet October 1, 1998
- Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Journal of Neuroscience August 1, 1988
- Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Journal of Pharmacology and Experimental Therapeutics 1987
- 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Journal of Neuroscience April 15, 1997
- Serotonin research: contributions to understanding psychoses TIPS - Trends in Pharmacological Sciences August 1, 2008
and 53 more in the library