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bioRxiv · 10.1101/2021.02.04.429772

Effects of LSD are differentially modulated in arrestin knockout mice

Rodriguiz, R. M.·Nadkarni, V.·Means, C. R.·Chiu, Y.-T.·Roth, B. L.·Wetsel, W. C.
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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 {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.

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Rodriguiz, R. M., Nadkarni, V., Means, C. R., Chiu, Y.-T., Roth, B. L., Wetsel, W. C.. 2021-02-06. Effects of LSD are differentially modulated in arrestin knockout mice. https://doi.org/10.1101/2021.02.04.429772

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