LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1
Ramona M. Rodriguiz, Vineet Nadkarni, Christopher R. Means, Vladimir M Pogorelov, Yi-Ting Chiu, Bryan L. Roth, William C. Wetsel
Scientific Reports September 5, 2021 DOI: 10.1038/s41598-021-96736-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice (wild-type, β-arrestin1-knockout, and β-arrestin2-knockout) |
| Interventions | Lysergic acid diethylamide (LSD) haloperidol |
| Topics | LSD |
| Citations | 92 |
| Key findings | LSD's psychedelic-like effects in mice require β-arrestin2 signaling through the 5-HT2A receptor. |
Abstract
Abstract Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, their hallucinogenic side-effects 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 these signaling modalities, we have used βArr1 and βArr2 mice. We find that LSD stimulates motor activities to similar extents in WT and βArr1-KO mice, without 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. By contrast, in βArr2-KO mice head twitch responses are low with LSD and this psychedelic is without effects on other surrogates. The 5-HT2AR antagonist MDL100907 (MDL) blocks the LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and βArr1-KOs, but not in βArr2-KOs. MDL restores LSD-mediated disruption of PPI in WT mice; haloperidol is required for normalization of PPI in βArr1-KOs. Collectively, these results reveal that LSD’s psychedelic drug-like actions appear to require βArr2.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 76
- Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Nature Neuroscience June 1, 2023
- The neural basis of psychedelic action. Nature Neuroscience October 24, 2022
- The promises and perils of psychedelic pharmacology for psychiatry. Nature Reviews Drug Discovery June 1, 2022
- Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nature Communications December 15, 2023
- Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity. Biochemistry January 21, 2022
and 71 more in the library
Cites 20
- Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences April 11, 2016
- Structural Features for Functional Selectivity at Serotonin Receptors Science March 21, 2013
- Structural Basis for Molecular Recognition at Serotonin Receptors Science March 22, 2013
- LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: A qualitative study of acute and sustained subjective effects Journal of Psychopharmacology November 11, 2014
- Serotonin research: contributions to understanding psychoses TIPS - Trends in Pharmacological Sciences August 1, 2008
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