Scientific Reports
September 5, 2021
Ramona M. Rodriguiz, Vineet Nadkarni, Christopher R. Means et al.
92 citations
Lysergic acid diethylamide (LSD) produces psychedelic effects through the 5-HT2A serotonin receptor, which activates both Gq and β-arrestin signaling pathways. Using mice lacking either β-arrestin1 or β-arrestin2, researchers found that LSD stimulated motor activities and psychedelic-like behaviors—including head twitches, grooming, retrograde walking, and nose-poking—in normal mice and those missing β-arrestin1, but not in mice missing β-arrestin2. The 5-HT2A antagonist MDL100907 blocked these effects. LSD also disrupted prepulse inhibition in normal and β-arrestin1-knockout mice, but not in β-arrestin2-knockouts. These findings indicate that LSD's psychedelic actions require β-arrestin2 signaling.
bioRxiv (Cold Spring Harbor Laboratory)
September 26, 2023
Yi-Ting Chiu, Wei Wang, Pierre Llorach et al.
15 citations
preprint
Psychedelic drugs such as LSD and psilocybin show promise as treatments for depression, anxiety, PTSD, migraine, and cluster headaches by activating the 5-HT2A receptor (HTR2A). Researchers engineered several new mouse lines to study the role of HTR2A and the neurons that express it. One line allows visualization of the receptor and identification of HTR2A-containing cells, providing a detailed anatomical map. Another line has a humanized version of the receptor, and a third enables targeted genetic manipulation. The mice exhibited expected behavioral responses to psychedelics, confirming their usefulness. Electrophysiology showed that serotonin increases firing of specific pyramidal neurons through HTR2A, consistent with the receptor's location on the cell surface. These tools will help clarify how psychedelics work at molecular, cellular, and behavioral levels.
bioRxiv Preprint Server
June 13, 2022
Isha Singh, Anubha Seth, Christian B. Billesbølle et al.
8 citations
preprint
The serotonin transporter (SERT) adopts three conformations, and most antidepressants target its outward-open state. Ibogaine, which targets the inward-open state, has an unusual antidepressant profile but is cardiotoxic. Computational docking of over 200 million small molecules against the ibogaine-stabilized inward-open SERT identified 36 top compounds; 13 inhibited SERT with potencies from 29 to 5000 nM. Optimization yielded two inhibitors with Ki values as low as 3 nM that stabilized an outward-closed state and showed little off-target activity. A cryo-EM structure confirmed the predicted binding geometry. In mice, both compounds showed anxiolytic and antidepressant activity with potencies up to 200 times greater than fluoxetine.
bioRxiv Preprint Server
February 4, 2021
Ramona M. Rodriguiz, Vineet Nadkarni, Christopher R. Means et al.
7 citations
preprint
Lysergic acid diethylamide (LSD) produces its psychedelic effects through the 5-HT2A serotonin receptor, which activates two signaling pathways: Gq and β-arrestin. Using mice lacking either β-arrestin1 or β-arrestin2, the authors show that LSD's psychedelic-like behaviors—head twitches, retrograde walking, nose poking, and disrupted prepulse inhibition—require β-arrestin2, not β-arrestin1. LSD also affects motor activity and body temperature in a β-arrestin-dependent manner. The 5-HT2A antagonist MDL100907 blocks these effects in wild-type mice, but in β-arrestin1-knockouts, haloperidol is needed to restore prepulse inhibition. These findings indicate that LSD's diverse behavioral actions are mediated through distinct β-arrestin subtypes, with β-arrestin2 necessary for its psychedelic-like effects.