Effects of the 5-HT_2A receptor antagonist volinanserin on head-twitch response and intracranial self-stimulation depression induced by different structural classes of psychedelics in rodents

Background: 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. Objectives: The present study explores the behavioral pharmacology of structurally distinct psychedelics in paradigms associated with serotonin 2A receptor (5-HT_2AR) activation and behavioral disruption in two rodent models. Utilizing the selective 5-HT_2AR antagonist volinanserin, we aimed to provide further pharmacological assessment of psychedelic effects in rodents. Methods: 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. Results: 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. Conclusion: Although hallucination-related HTR behavior induced by phenethylamine, ergoline, and tryptamine psychedelics appears to be 5-HT_2AR-mediated, the receptor(s) responsible for behavioral disruptive effects may differ among these three structural classes.