Effects of LSD are differentially modulated in arrestin knockout mice

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 {beta}-arrestin-({beta}Arr) mediated signaling. To separate effects of these signaling modes, we have used {beta}Arr1 and {beta}Arr2 mice. We find that LSD stimulates motor activities to similar extents in WT and {beta}Arr1-KO mice, with non-significant effects in {beta}Arr2-KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose poking in WT and {beta}Arr1-KO animals. In contrast, LSD only slightly stimulates head twitches in {beta}Arr2-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 {beta}Arr1-KOs; PPI is unaffected in {beta}Arr2-KOs. MDL restores PPI in WT mice, but this antagonist is without effect and haloperidol is required in {beta}Arr1-KOs. LSD produces a biphasic body-temperature response in WT mice, a monophasic response in {beta}Arr1-KOs, and is without effect in {beta}Arr2 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 {beta}Arr1-KOs. Collectively, these results reveal that LSD produces diverse behavioral effects through {beta}Arr1 and {beta}Arr2, and that LSDs psychedelic drug-like actions appear to require {beta}Arr2.