LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1
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 it...
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| Format: | Article |
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Nature Portfolio
2021-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-96736-3 |
| _version_ | 1818683745422540800 |
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| author | Ramona M. Rodriguiz Vineet Nadkarni Christopher R. Means Vladimir M. Pogorelov Yi-Ting Chiu Bryan L. Roth William C. Wetsel |
| author_facet | Ramona M. Rodriguiz Vineet Nadkarni Christopher R. Means Vladimir M. Pogorelov Yi-Ting Chiu Bryan L. Roth William C. Wetsel |
| author_sort | Ramona M. Rodriguiz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T10:39:37Z |
| format | Article |
| id | doaj.art-3215b394370e440fb5ba82da17d03128 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-17T10:39:37Z |
| publishDate | 2021-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-3215b394370e440fb5ba82da17d031282022-12-21T21:52:17ZengNature PortfolioScientific Reports2045-23222021-09-0111111410.1038/s41598-021-96736-3LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1Ramona M. Rodriguiz0Vineet Nadkarni1Christopher R. Means2Vladimir M. Pogorelov3Yi-Ting Chiu4Bryan L. Roth5William C. Wetsel6Department of Psychiatry and Behavioral Sciences, Duke University Medical CenterDepartment of Psychiatry and Behavioral Sciences, Duke University Medical CenterDepartment of Psychiatry and Behavioral Sciences, Duke University Medical CenterDepartment of Psychiatry and Behavioral Sciences, Duke University Medical CenterDivision of Chemical Biology and Medicinal Chemistry, Department of Pharmacology, Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill School of MedicineDivision of Chemical Biology and Medicinal Chemistry, Department of Pharmacology, Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill School of MedicineDepartment of Psychiatry and Behavioral Sciences, Duke University Medical CenterAbstract 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.https://doi.org/10.1038/s41598-021-96736-3 |
| spellingShingle | Ramona M. Rodriguiz Vineet Nadkarni Christopher R. Means Vladimir M. Pogorelov Yi-Ting Chiu Bryan L. Roth William C. Wetsel LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1 Scientific Reports |
| title | LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1 |
| title_full | LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1 |
| title_fullStr | LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1 |
| title_full_unstemmed | LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1 |
| title_short | LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1 |
| title_sort | lsd stimulated behaviors in mice require β arrestin 2 but not β arrestin 1 |
| url | https://doi.org/10.1038/s41598-021-96736-3 |
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