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

This mice study finds that, using mice with specific receptor deficiencies, the signals are β-arrestin-2 (βArr; type of protein important in signalling) mediated, but not βarr1 mediated. This line of evidence points towards the requirement of βArr2 for LSD’s psychedelic effects.

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.”

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

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

LSD is a prototypical psychedelic drug that alters sensation, perception, thought, mood, sense of time and space, and consciousness of self in humans. It has been used to treat cluster headaches, anxiety and depressive disorders in life-threatening conditions, and may have potential for studying human consciousness.

LSD shares structural similarities to 5-HT1 and has high affinities for all thirteen 5-HT G protein coupled receptors (GPCRs). Its hallucinogenic actions are ascribed to 5-HT2A receptor stimulation and are blocked by the 5-HT2AR preferring antagonist ketanserin.

LSD activates G protein signaling at many GPCRs, but it stimulates Arr-mediated responses at most tested biogenic amine GPCRs8, and global Arr1 and Arr2 knockout (KO) mice have been generated to determine whether LSD produces behavioral effects that are differential among the wild-type (WT) and Arr1-KO, and WT and Arr2-KO mice.

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Find this paper

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

https://doi.org/10.1038/s41598-021-96736-3

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Study details

Compounds studied
LSD

Topics studied
Neuroscience

Study characteristics
Animal Study Bio/Neuro

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