5-HT2CR Is as Important as 5-HT2AR in Inducing Hallucinogenic Effects in Serotonergic Compounds

Introduction

Hallucinogens such as mescaline act on serotonergic systems and have long been associated with activation of serotonin (5-HT) 2A receptors (5-HT2AR), with frontal cortex-dependent head‑twitch response (HTR) in rodents commonly used as a preclinical proxy for hallucinogenic activity. Although genetic or pharmacological inactivation of 5-HT2AR blocks HTR and other psychedelic behaviours, not all 5-HT2AR agonists produce hallucinogenic effects, and other 5-HT receptor subtypes have been implicated, including 5-HT1A and 5-HT2C receptors (5-HT2CR). Recent anatomical work shows co‑localisation of 5-HT2AR and 5-HT2CR in apical dendrites of medial prefrontal cortex pyramidal neurons, and prior genetic deletion work suggests 5-HT2CR contributes to the behavioural effects of some phenethylamines, leaving open the question whether 5-HT2AR activation alone is sufficient to explain psychedelic effects. Custodio and colleagues set out to reassess the relative roles of 5-HT2AR and 5-HT2CR by combining receptor binding and transporter assays with in vivo pharmacology and neurochemical measures. Using two mescaline derivatives, methallylescaline (MAL; a 3,4,5-trisubstituted analogue) and BOD (a 2,4,5-trisubstituted analogue), the study examines receptor affinities, SERT uptake inhibition, HTR with pharmacological antagonism, downstream signalling, neurochemical endpoints (TPH2 and 5-HT levels) and behavioural indices of neurotoxicity in mice. The paper is a preprint and has not been peer reviewed.