Lysergic acid diethylamide (LSD) produces psychedelic effects through the 5-HT2A serotonin receptor, which activates both Gq and β-arrestin signaling pathways. Using mice lacking either β-arrestin1 or β-arrestin2, researchers found that LSD stimulated motor activities and psychedelic-like behaviors—including head twitches, grooming, retrograde walking, and nose-poking—in normal mice and those missing β-arrestin1, but not in mice missing β-arrestin2. The 5-HT2A antagonist MDL100907 blocked these effects. LSD also disrupted prepulse inhibition in normal and β-arrestin1-knockout mice, but not in β-arrestin2-knockouts. These findings indicate that LSD's psychedelic actions require β-arrestin2 signaling.
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.