• Chunyang Dong, Calvin Ly, Lee E Dunlap, Maxemiliano V Vargas, Junqing Sun, In-Wook Hwang, Arya Azinfar, Won Chan Oh, William C Wetsel, David E Olson, and Lin Tian.
• Graduate Program in Biochemistry, Molecular, Cellular, Developmental Biology, University of California, Davis, Davis, CA 95616, USA; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, USA.
• Cell. 2021 May 13; 184 (10): 2779-2792.e18.

AbstractLigands can induce G protein-coupled receptors (GPCRs) to adopt a myriad of conformations, many of which play critical roles in determining the activation of specific signaling cascades associated with distinct functional and behavioral consequences. For example, the 5-hydroxytryptamine 2A receptor (5-HT2AR) is the target of classic hallucinogens, atypical antipsychotics, and psychoplastogens. However, currently available methods are inadequate for directly assessing 5-HT2AR conformation both in vitro and in vivo. Here, we developed psychLight, a genetically encoded fluorescent sensor based on the 5-HT2AR structure. PsychLight detects behaviorally relevant serotonin release and correctly predicts the hallucinogenic behavioral effects of structurally similar 5-HT2AR ligands. We further used psychLight to identify a non-hallucinogenic psychedelic analog, which produced rapid-onset and long-lasting antidepressant-like effects after a single administration. The advent of psychLight will enable in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and the development of 5-HT2AR-dependent non-hallucinogenic therapeutics.Copyright © 2021 Elsevier Inc. All rights reserved.

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