“Psychedelic-Inspired Drug Discovery Using an Engineered Biosensor”, 2021-05-13 (; backlinks; similar):
Engineered psychLight—a genetically encoded 5-HT sensor based on the 5-HT2AR
PsychLight can measure 5-HT dynamics in behaving mice
A psychLight-based cellular imaging platform predicts hallucinogenic potential
Identified a non-hallucinogenic psychedelic analog with antidepressant properties
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.
[Keywords: genetically encoded indicators, serotonin, serotonin receptors, psychedelic, hallucinogen, depression]