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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study using knockout mice |
|---|---|
| Population | Wild-type, β-arrestin1-knockout, and β-arrestin2-knockout mice |
| Interventions | Lysergic acid diethylamide (LSD) haloperidol |
| Topics | LSD |
| Citations | 7 |
| Key findings | LSD's psychedelic-like behavioral effects require β-arrestin2 signaling, not β-arrestin1. |
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.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 6
- Structure-based discovery of nonhallucinogenic psychedelic analogs Science January 27, 2022
- Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications International Journal of Molecular Sciences November 16, 2022
- Pharmahuasca and DMT Rescue ROS Production and Differentially Expressed Genes Observed after Predator and Psychosocial Stress: Relevance to Human PTSD. ACS Chemical Neuroscience January 6, 2022
- Structural basis of psychedelic LSD recognition at dopamine D1 receptor. Neuron October 9, 2024
- Evaluation of Hippocampal Allostatic Load-Associated Factors in Animal Models of Post-Traumatic Stress Disorder: Relevance to Human PTSD March 2, 2022
and 1 more in the library
Cites 24
- 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
and 19 more in the library