At the University of California (UC), Davis, psychLight just dropped in to see what condition serotonin dynamics was in. And psychLight didn’t even have to fly eight miles high. Upon binding serotonin or a hallucinogenic ligand, all psychLight had to do was undergo a conformation change that was accompanied by an increase in fluorescence.

Essentially, psychLight is a genetically encoded fluorescent sensor. By showing how a psychedelic or psychedelic-like compound may interact with the serotonin 2A receptor, the sensor can reveal the compound’s hallucinogenic potential. This possibility has been demonstrated in experiments that evaluated cultured neurons in which psychLight was transiently expressed.

Psychedelic-like drugs that target the serotonin 2A receptor have shown promise for treating neuropsychiatric disorders such as depression, post-traumatic stress disorder, and substance use disorder. However, these drugs can also cause hallucinations, which are usually unwelcome in medical settings.

To distinguish between psychedelic-like drugs that will cause hallucinations and those that won’t, drug developers currently rely on the “head twitch” response assay in rodents. Unfortunately, this assay is inadequate for directly assessing the status of the serotonin 2A receptor both in vitro and in vivo, the UC Davis scientists noted.

A better assay may now be possible with psychLight, which resembles the serotonin 2A receptor but incorporates a fluorescent component. When psychLight binds to serotonin or a hallucinogenic ligand it changes its conformation, causing the fluorescence to increase. Non-hallucinogenic ligands can also bind to psychLight but lead to a different fluorescence profile.

This image shows a simulated structure of psychLight consisting of the serotonin 2A receptor (gray), a linker (magenta), and a cpGFP (green). [Chunyang Dong, Calvin Ly, and Joanne Ly at UC Davis]

Details about psychLight appeared April 28 in the journal Cell, in an article titled, “Psychedelic-inspired drug discovery using an engineered biosensor.”

“PsychLight detects behaviorally relevant serotonin release and correctly predicts the hallucinogenic behavioral effects of structurally similar 5-hydroxytryptamine 2A receptor ligands,” the article’s authors wrote. “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.

Researchers could use psychLight to see how naturally occurring neuromodulators like serotonin, or hallucinogenic drugs, act on different parts of the brain. They could also use it to screen candidate drugs for those which activate the serotonin 2A receptor and could cause hallucinations. When psychLight is expressed in cells and those cell cultures are exposed to a hallucinogenic drug, they light up.

The study’s authors asserted that psychLight could enable in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and the development of serotonin 2A receptor–dependent non-hallucinogenic therapeutics.

“Serotonin reuptake inhibitors have long been used for treating depression, but we don’t know much about their mechanism. It’s like a black box,” said Lin Tian, PhD, one of the senior authors of the study and an associate professor of biochemistry and molecular medicine at UC Davis. “This sensor allows us to image serotonin dynamics in real time when animals learn or are stressed and visualize the interaction between the compound of interest and the receptor in real time.”

Tian’s lab, which develops fluorescent indicators for neural chemicals in the brain such as serotonin and dopamine, joined forces with the lab of David E. Olson, PhD, the study’s other senior author and an assistant professor of chemistry at UC Davis.

“My lab is really interested in the serotonin 2A receptor, which is the target of both psychedelic drugs and classic antipsychotics,” Olson noted. “Lin’s lab is a leader in developing sensors for neuromodulators like serotonin. It just made perfect sense for us to tackle this problem together.”

Experts believe that one of the benefits of using psychedelic drugs over existing drugs is that they appear to promote neural plasticity—essentially allowing the brain to rewire itself. If proven effective, this approach could lead to a drug that works in a single dose or a small number of doses, rather than having to be taken indefinitely. But one thing that researchers don’t know is whether patients would be able to gain the full benefit of neural plasticity without undergoing the “psychedelic trip” part of the treatment.

In the Cell article, the investigators reported that they used psychLight to identify a compound called AAZ-A-154, a previously unstudied molecule that has the potential to act on beneficial pathways in the brain without hallucinogenic effects. “One of the problems with psychedelic therapies is that they require close guidance and supervision from a medical team,” Olson remarked. “A drug that doesn’t cause hallucinations could be taken at home.”

The serotonin 2A receptor belongs to a class of receptors called G protein-coupled receptors (GPCRs). “More than one-third of all FDA-approved drugs target GPCRs, so this sensor technology has broad implications for drug development,” Tian observed. “The special funding mechanisms of BRAIN Initiative from the National Institutes of Health allowed us to take a risky and radical approach to developing this technology, which could open the door to discovering better drugs without side effects and studying neurochemical signaling in the brain.”

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