Fluorescent Sensor Identifies Psychiatric Drugs

A genetically encoded biosensor to detect hallucinogenic compounds could be used to aid in the discovery of treatments for mental illness, in neuroscience research, and to detect drugs of abuse. A team at the University of California, Davis (UC Davis) developed the sensor, called psychLight, which can be used to look for pharmaceutical potential without the side effect of hallucinations.

Compounds related to psychedelic drugs such as LSD and DMT show promise in the treatment of depression, post-traumatic stress disorder, and substance abuse disorder. The drugs, called psychoplastogens, rapidly alter brain connections. These drugs can also cause hallucinations and require careful use and patient monitoring.

Currently, the most effective way to test an experimental drug to see if it causes hallucinations is the “head twitch” assay in rodents.

“Scientific studies on psychedelic drugs have been conducted since the 1940s, but we still don’t have an effective cellular assay for them,” said David Olson, assistant professor in the Department of Chemistry, College of Letters and Science at UC Davis, and a co-author of the paper that introduced the sensor.

The sensor is based on the serotonin 2A receptor (HT_2AR); serotonin that is released from neurons in the brain and picked up by serotonin receptors on other neurons acts to regulate mood. Psychedelic drugs and drugs that are used to treat psychiatric disorders act through the serotonin 2A receptor.

Dissociated neurons expressing psychLight. Courtesy of Chunyang Dong, Calvin Ly, and Joanne Ly at UC Davis.

The researchers engineered a modified version of the HT_2A receptor with a fluorescent component. When psychLight binds to serotonin or a hallucinogenic ligand, it changes its conformation and causes the fluorescent component to increase. The researchers said that nonhallucinogenic ligands can also bind to psychLight, but lead to a different fluorescence profile.

The team could also use it to screen candidate drugs for those that activate the HT_2A receptor and could cause hallucinations as a result. When psychLight is expressed in cells and those cell cultures are exposed to a hallucinogenic drug, they light up. To screen compounds for hallucinogenic activity and for binding of the HT_2A receptor, the researchers set up a high-throughput system to use cells that expressed psychLight. Tests showed that a previously untested compound called AAZ-A-154 activated the receptor, but it is not hallucinogenic. Subsequent tests showed the compound does show promise as an antidepressant.

UC Davis InnovationAccess and the company Seven Biosciences are working to license the psychLight technology and develop it for commercial use.

The National Institutes of Health, a Hellman Fellowship, and the UC Davis STAIR grant program supported the work. The research was published in Cell.