Psychedelic-inspired drug discovery using an engineered biosensor

This study describes the development and use of an engineered biosensor (PsychLight) that detects relevant serotonin release to predict the hallucinogenic behavioral effects of psychedelics. This tool is used to identify non-hallucinogenic psychedelic compounds that still elicit antidepressant-like effects.

Abstract

“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.”

Authors: 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 & Lin Tian

Notes

This research was highlighted in Nature News. A researcher, not affiliated with the current group, said the method is an “innovative approach” but that the translation from research in mice to men is always a difficult bridge to gap.

You can also find a breakdown on The Tab.

Highlights from the authors/journal:

  • 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

PsychLight is a sensor that can highlight activity at our most psychedelic of receptors. This paper describes how the sensor works and how it has already been used to identify promising molecules.

The sensor works by lighting up when psychedelic molecules bind to it. And lighting up is meant literally, the sensor is fluorescent. The structure of the receptor is near-identical to the serotonin (5HT) 2a receptor. This makes it so that psychedelics which usually bind to this receptor, also bind to the sensor. The big difference is that PsychLight, well, lights up if this happens.

Highlights from the paper

  • The researchers inserted the sensor in the brains of mice and then gave them a variety of psychedelics, which lit up the sensor
  • But when given ketanserin, something that blocks psychedelics, the sensor didn’t light up, even if psychedelics were given afterwards
  • The research group also tested novel compounds and found that ‘AAZ-A-154’ didn’t light up the sensor, but did show promising neurogenesis effects

With the caveat of this study being in mice, this sensor could become a vital tool in the identification of new psychedelics. These can be molecules that can possibly help heal mental health disorders, possibly without the acute trip.

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