Effects of the 5-HT2A receptor antagonist volinanserin on head-twitch response and intracranial self-stimulation depression induced by different structural classes of psychedelics in rodents.
Alaina M Jaster, Harrison J. Elder, Samuel A Marsh, Mario de la Fuente Revenga, S Stevens Negus, Javier González-Maeso
Psychopharmacology June 1, 2022 DOI: 10.1007/s00213-022-06092-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice and rats |
| Interventions | volinanserin DOI LSD mescaline psilocybin salvinorin A |
| Dose | 0.0001-0.1 mg/kg volinanserin; 1.0 mg/kg DOI; 0.32 mg/kg LSD |
| Topics | Depression Serotonin |
| Keywords | Ergolines Hallucinogens Intracranial self-stimulation icss Phenethylamines Psychedelics Serotonin 5-ht2a receptor Tryptamines Volinanserin Psychedelic psychopharmacology psychopharmacology |
| Citations | 41 |
| Key points | Hallucination-related head-twitch behavior induced by phenethylamine, ergoline, and tryptamine psychedelics is mediated by the serotonin 2A receptor, but the receptors responsible for behavioral disruptive effects may differ among these three structural classes. |
Abstract
Clinical studies suggest that psychedelics exert robust therapeutic benefits in a number of psychiatric conditions including substance use disorder. Preclinical studies focused on safety and efficacy of these compounds are necessary to determine the full range of psychedelics' effects. The present study explores the behavioral pharmacology of structurally distinct psychedelics in paradigms associated with serotonin 2A receptor (5-HT2AR) activation and behavioral disruption in two rodent models. Utilizing the selective 5-HT2AR antagonist volinanserin, we aimed to provide further pharmacological assessment of psychedelic effects in rodents. We compared volinanserin (0.0001-0.1 mg/kg) antagonism of the phenethylamine 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1.0 mg/kg) and the ergoline lysergic acid diethylamide (LSD, 0.32 mg/kg) in preclinical assays predictive of hallucinations (head-twitch response or HTR in mice) and behavioral disruption (intracranial self-stimulation or ICSS in rats). Volinanserin antagonism of the phenethylamine mescaline, the tryptamine psilocybin, and the k-opioid receptor agonist salvinorin A was also evaluated in the rat ICSS assay. Volinanserin had similar potency, effectiveness, and time-course to attenuate DOI-induced HTR in mice and ICSS depression in rats. Volinanserin completely blocked LSD-induced HTR in mice, but not LSD-induced ICSS depression in rats. Volinanserin also reversed ICSS depression by mescaline, but it was only partially effective to reduce the effects of psilocybin, and it exacerbated ICSS depression by salvinorin A. Although hallucination-related HTR behavior induced by phenethylamine, ergoline, and tryptamine psychedelics appears to be 5-HT2AR-mediated, the receptor(s) responsible for behavioral disruptive effects may differ among these three structural classes.
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 36
- Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action. Journal of Neuroscience November 8, 2023
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews November 30, 2023
- Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications International Journal of Molecular Sciences November 16, 2022
- Differences across sexes on head-twitch behavior and 5-HT2A receptor signaling in C57BL/6J mice. Neuroscience Letters September 25, 2022
- Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics. Molecular Psychiatry September 1, 2023
and 31 more in the library
Cites 55
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- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
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- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
and 50 more in the library