LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1

Introduction

Rodriguiz and colleagues frame their study around the observation that psychedelic drugs such as LSD produce profound alterations in perception and cognition and have shown therapeutic promise for conditions including anxiety, depression, and substance-use disorders. LSD is known to act at many serotonin G protein-coupled receptors (GPCRs) and its hallucinogenic actions have been attributed primarily to activation of the 5-HT2A receptor (5-HT2AR). At the molecular level, 5-HT2AR engagement can initiate both Gq-mediated G protein signalling and arrestin-dependent (β-arrestin, βArr) pathways, and earlier work indicates LSD shows bias towards β-arrestin-mediated signalling at this receptor. The introduction notes that both non-visual arrestins, βArr1 and βArr2, are expressed in 5-HT2AR-containing neurons and that global knockout mouse lines for Arrb1 and Arrb2 are available, creating an opportunity to dissect the roles of each arrestin isoform in LSD-evoked behaviours. The present study set out to determine whether behavioural surrogates of psychedelic drug actions in mice depend on βArr1 or βArr2. Using global βArr1-KO and βArr2-KO mice and their wild-type littermates, the investigators compared LSD effects across a battery of behaviours commonly used as rodent proxies for psychedelic action (locomotion, head-twitch response, grooming and its organisation, retrograde walking, nose-poking) and on sensorimotor gating measured by prepulse inhibition (PPI). They also assessed 5-HT2AR expression by radioligand binding and immunofluorescence to check whether any behavioural differences could be explained by receptor-level changes. The work aims to clarify whether β-arrestin signalling is necessary for LSD-stimulated behaviours and, if so, which arrestin isoform is required.