LSD’s effects are differentially modulated in arrestin knockout mice

Lysergic acid diethylamide (LSD) produces its psychedelic effects through the 5-HT2A serotonin receptor, which activates two signaling pathways: Gq and β-arrestin. Using mice lacking either β-arrestin1 or β-arrestin2, the authors show that LSD's psychedelic-like behaviors—head twitches, retrograde walking, nose poking, and disrupted prepulse inhibition—require β-arrestin2, not β-arrestin1. LSD also affects motor activity and body temperature in a β-arrestin-dependent manner. The 5-HT2A antagonist MDL100907 blocks these effects in wild-type mice, but in β-arrestin1-knockouts, haloperidol is needed to restore prepulse inhibition. These findings indicate that LSD's diverse behavioral actions are mediated through distinct β-arrestin subtypes, with β-arrestin2 necessary for its psychedelic-like effects.

Study at a glance

Abstract

Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, the hallucinogenic side-effects of psychedelics 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 effects of these signaling modes, we have used βArr1 and βArr2 mice. We find that LSD stimulates motor activities to similar extents in WT and βArr1-KO mice, with non-significant 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. In contrast, LSD only slightly stimulates head twitches in βArr2-KO mice, without effects on retrograde walking or nose poking. The 5-HT2AR antagonist MDL100907 (MDL) blocks these LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and βArr1-KOs; PPI is unaffected in βArr2-KOs. MDL restores PPI in WT mice, but this antagonist is without effect and haloperidol is required in βArr1-KOs. LSD produces a biphasic body-temperature response in WT mice, a monophasic response in βArr1-KOs, and is without effect in βArr2 mutants. Both MDL and the 5-HT1AR antagonist, WAY 100635 (WAY), block the effects of LSD on body temperatures in WT mice, whereas WAY is effective in βArr1-KOs. Collectively, these results reveal that LSD produces diverse behavioral effects through βArr1 and βArr2, and that LSD’s psychedelic drug-like actions appear to require βArr2.