LSD-stimulated behaviors in mice require \u03b2-arrestin 2 but not \u03b2-arrestin 1

Ramona M Rodriguiz,Christopher R Means,William C Wetsel,Vineet Nadkarni,Yi-Ting Chiu,Bryan L Roth,Vladimir M Pogorelov

doi:10.1038/s41598-021-96736-3

Abstract

Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, their hallucinogenic side-effects often preclude their clinical use. Lysergic acid diethylamide (LSD) is a prototypical hallucinogen and its psychedelic actions are exerted through the 5-HT2A serotonin receptor (5-HT2AR). 5-HT2AR activation stimulates Gq- and β-arrestin- (βArr) mediated signaling. To separate these signaling modalities, we have used βArr1 and βArr2 mice. We find that LSD stimulates motor activities to similar extents in WT and βArr1-KO mice, without effects in βArr2-KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose-poking in WT and βArr1-KO animals. By contrast, in βArr2-KO mice head twitch responses are low with LSD and this psychedelic is without effects on other surrogates. The 5-HT2AR antagonist MDL100907 (MDL) blocks the LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and βArr1-KOs, but not in βArr2-KOs. MDL restores LSD-mediated disruption of PPI in WT mice; haloperidol is required for normalization of PPI in βArr1-KOs. Collectively, these results reveal that LSD’s psychedelic drug-like actions appear to require βArr2.

Highlights

Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans
Since Lysergic acid diethylamide (LSD) is βArr biased at the 5-HT2A serotonin receptor (5-HT2AR), the present investigations were conducted to determine whether LSD produces behavioral effects that were differential among the wild-type (WT) and β-arrestin 1 (βArr1)-KO, and WT and βArr2-KO mice
The Arrb[1] or Arrb[2] genes were obtained from 129 libraries, the constructs were injected into ES cells that were microinjected into C57BL/6 b lastocysts[30,31]

Summary

Introduction

Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. Since LSD-induced states bear many similarities to early acute phases of psychosis[2] and because serotonin (5-HT) and LSD both contain an indolamine moiety, Woolley and S haw[3] proposed that aberrant 5-HT levels in brain may produce mental disturbances including psychosis This suggestion gave rise to the 5-HT hypothesis for schizophrenia and stimulated researchers to study LSD in hopes of gaining a better understanding of the disorder. LSD activates G protein signaling at many GPCRs10, this psychedelic stimulates βArr-mediated responses at most tested biogenic amine GPCRs8. Since LSD is βArr biased at the 5-HT2AR, the present investigations were conducted to determine whether LSD produces behavioral effects that were differential among the wild-type (WT) and βArr1-KO, and WT and βArr2-KO mice

Methods

Results

Conclusion