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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 its psychedelic actions are exerted through the 5-HT_2A 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.

SUBMITTER: Rodriguiz RM

PROVIDER: S-EPMC8417039 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1.

Rodriguiz Ramona M RM Nadkarni Vineet V Means Christopher R CR Pogorelov Vladimir M VM Chiu Yi-Ting YT Roth Bryan L BL Wetsel William C WC

Scientific reports 20210903 1

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-HT<sub>2A</sub> serotonin receptor (5-HT2AR). 5-HT2AR activation stimulates Gq- and β-arrestin- (βArr) mediated signaling. To separate these signaling modalities ...[more]

PMID: 34480046

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Project description:RationaleAbdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII), and previous studies indicated a primary role for the AngII type 1a receptor in AAA formation. β-arrestin (βarr)-2 is a multifunctional scaffolding protein that binds G-protein-coupled receptors such as AngII type 1a and regulates numerous signaling pathways and pathophysiological processes. However, a role for βarr2 in AngII-induced AAA formation is currently unknown.ObjectiveTo determine whether βarr2 played a role in AngII-induced AAA formation in mice.Methods and resultsTreatment of βarr2(+/+) and βarr2(-/-) mice on the hyperlipidemic apolipoprotein E-deficient (apoE(-/-)) background or on normolipidemic C57BL/6 background with AngII for 28 days indicated that βarr2 deficiency significantly attenuated AAA formation. βarr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2, monocyte chemoattractant protein-1, macrophage inflammatory protein 1α, and macrophage infiltration. AngII also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 in apoE(-/-)/βarr2(+/+) aortas, whereas βarr2 deficiency diminished this increase. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 activation with CI1040 (100 mg/kg per day) reduced the level of AngII-induced cyclooxygenase-2 expression in apoE(-/-)/βarr2(+/+) mice to the level observed in apoE(-/-)/βarr2(-/-) mice. AngII treatment also increased matrix metalloproteinase expression and disruption of the elastic layer in apoE(-/-)/βarr2(+/+) aortas, and βarr2 deficiency reduced these effects.Conclusionsβarr2 contributes to AngII-induced AAA formation in mice by phosphorylated extracellular signal-regulated kinase 1/2-mediated cyclooxygenase-2 induction and increased inflammation. These studies suggest that for the AngII type 1a receptor, G-protein-independent, βarr2-dependent signaling plays a major role in AngII-induced AAA formation.

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LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1.

Publications

LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1.

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