LSD’s effects are differentially modulated in arrestin knockout mice
Ramona M. Rodriguiz, Vineet Nadkarni, Christopher R. Means, Yi-Ting Chiu, Bryan L. Roth, William C. Wetsel
bioRxiv Preprint Server February 4, 2021 preprint DOI: 10.1101/2021.02.04.429772 via bioRxiv
Summary
LSD produces various behavioral effects, including motor stimulation and alterations in body temperature, through different signaling pathways involving βArr1 and βArr2 proteins. In wild-type and βArr1 knockout mice, LSD induces significant behaviors like head twitches and grooming, while these effects are diminished in βArr2 knockout mice. The 5-HT2AR antagonist MDL100907 blocks LSD's effects, indicating that βArr2 is crucial for LSD's psychedelic actions.
Study at a glance
| Population | mice, specifically wild-type and knockout models for βArr1 and βArr2 |
|---|---|
| Key finding | LSD's psychedelic drug-like actions appear to require βArr2, as its effects are significantly reduced in βArr2 knockout mice. |
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.