期刊
CELL
卷 184, 期 10, 页码 2779-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2021.03.043
关键词
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资金
- Biological Analysis Core of the UC Davis MIND Institute Intellectual and Development Disabilities Research Center [U54 HD079125]
- National Insitute of Health [R01GM128997, DP2MH107056, U01NS090604, U01NS013522, U01NS103571, R01MH101214, R01MH12478, R21MH126073]
- Hellman Fellowship
- Human Frontier Fellowship
- Rita Allen Investigator Award
- UC Davis
- National Institute Healthy training grants [T32GM113770, 5T32GM099608]
- Brain and Behavior Research Foundation NARSAD Young Investigator Award
- Brain Research Foundation Seed Grant
The study introduces psychLight, a genetically encoded fluorescent sensor based on the structure of 5-HT2AR, which can detect behaviorally relevant serotonin release and predict the effects of different 5-HT2AR ligands. This new technology identified a non-hallucinogenic psychedelic analog with rapid-onset and long-lasting antidepressant-like effects.
Ligands 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.
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