LSD’s effects are differentially modulated in arrestin 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 5HT2A serotonin receptor (5HT2AR). 5HT2AR activation stimulates Gq and arrestin (Arr) mediated signaling. To separate effects of these signaling modes, we have used Arr1 and Arr2 mice. We find that LSD stimulates motor activities to similar extents in WT and Arr1 KO mice, with non-significant effects in Arr2 KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose poking in WT and Arr1 KO animals. In contrast, LSD only slightly stimulates head twitches in Arr2 KO mice, without effects on retrograde walking or nose poking. The 5HT2AR antagonist MDL100907 (MDL) blocks these LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and Arr1 KOs. PPI is unaffected in Arr2 KOs. MDL restores PPI in WT mice, but this antagonist is without effect and haloperidol is required in Arr1 KOs. LSD produces a biphasic body-temperature response in WT mice, a monophasic response in Arr1 KOs, and is without effect in Arr2 mutants. Both MDL and the 5HT1AR antagonist, WAY100635 (WAY), block the effects of LSD on body temperatures in WT mice, whereas WAY is effective in Arr1 KOs. Collectively, these results reveal that LSD produces diverse behavioral effects through Arr1 and Arr2, and that the psychedelic drug-like actions of LSD appear to require Arr2.

Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 receptors in the head twitch response induced by 5-hydroxytryptophan and psilocybin: Translational implications

“…We have categorized the effect on HTR induction by 5-HTP and PSIL of pre-treatment with 5-HT2A and 5-HT2C antagonists and a 5-HT1A agonist. We found complete ablation of HTR induced by 5-HTP and PSIL following pre-treatment with the 5-HT2A antagonist M100907, similar to the effect of M100907 on HTR induced by DOI (Canal et al, 2013; de la Fuente Revenga et al, 2020), 2-CI (Halberstadt and Geyer, 2014), N,N-dipropyltryptamine (DPT) (Fantegrossi et al, 2008), and LSD (Brandt et al, 2016; Rodriguiz et al, 2021; Jaster et al, 2022). The 5-HT1A agonist, 8-OH-DPAT, significantly attenuated HTR induced by 5-HTP and PSIL.…”

Pharmahuasca and DMT Rescue ROS Production and Differentially Expressed Genes Observed after Predator and Psychosocial Stress: Relevance to Human PTSD

“…Psychedelics, including DMT, induce 5-HT 2A R-dependent structural neuroplasticity, comparable to the recently FDA-approved antidepressant NMDAR antagonist, ketamine. ,,, In vitro experiments with lysergic acid diethylamide and ketamine suggest that there are two requisite phases for the induction of neuroplasticity, an initial “stimulation” phase and a secondary “growth” phase . Existing evidence suggests that serotonergic psychedelics activate 5-HT 2A R through unique functional selectivity, which leads to the selective recruitment of GPCR effectors (Figures S9 and S10) and β-arrestin 1,2, depending on the compound. , This leads to the stimulation phase through increased AMPAR ( Gria1 ) activation, likely through elevated calcium signaling downstream of Gαq, triggering brain-derived neurotropic factor release, and the initial induction of a plastic state through TrkB receptors. Subsequently, the growth phase is initiated through activation of mTOR complex 1 and/or 2 (mTORC1, mTORC2), which we observed to be transcriptionally upregulated by DMT and pharmahuasca (Figure ), leading to CREB pathway activation, which we also observed to be upregulated by pharmahuasca , (Figure S12).…”

Structure-based discovery of nonhallucinogenic psychedelic analogs

“…Lisuride lacks comparable psychoactive properties in humans and also fails to induce the HTR in mice ( 32 , 33 ). Previously, genetic deletion of β-arrestin2 was found to decrease responsiveness to l -5-hydroxytryptophan and LSD-induced HTR ( 34 , 35 ). However, 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), another commonly used psychedelic that shows greatly attenuated HTR in G q knockout mice ( 36 ), produced an HTR of equal magnitude in wild-type and β-arrestin2 knockout mice ( 37 ).…”