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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

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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.

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This work was supported in part by National Institute of Health (NIH) R01MH084894 (J.G.-M.), R01MH111940 (J.G.-M.), P30DA033934 (S.S.N. and J.G.-M.), and T32MH020030 (M.d.l.F.R.).

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Conceived and designed experiments, analyzed the data, and wrote the manuscript: A.M.J., H.E., S.S.N, and J.G.-M. Performed experiments: A.M.J., H.E., and S.A.M. Supervised the research and obtained funding: J.G.-M. and S.S.N. Provided advice on behavioral assays and editorial suggestions on early drafts of the report: M.d.l.F.R. All authors discussed the results and commented on the manuscript prior to submission for publication consideration.

Corresponding authors

Correspondence to S. Stevens Negus or Javier González-Maeso.

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Ethics approval

Experiments were conducted in accord with NIH guidelines and were approved by the Virginia Commonwealth University Animal Care and Use Committee.

Conflict of interest

J.G.-M. has a sponsored research contract with NeuRistic, and M.d.l.F.R. has a consulting agreement with Noetic Fund. The remaining authors declare that they have no conflict of interest.

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This article belongs to a Special Issue on Psychopharmacology on Psychedelic Drugs

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Jaster, A.M., Elder, H., Marsh, S.A. et al. 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. Psychopharmacology 239, 1665–1677 (2022).

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