Psychedelics stimulate hippocampal cells to reduce anxiety, study finds

A classic psychedelic, similar to LSD, psilocybin and mescaline, activates a type of cell in the brain that silences other nearby neurons, a finding that offers insight into how these drugs reduce anxiety, a new study finds.

The results show that the psychedelic DOI (2,5-dimethoxy-4-iodoamphetamine) reduces anxiety in mice and rats while activating the ventral hippocampus and so-called fast-spiking interneurons.

“It’s not clear what areas of the brain and what cell types are involved when psychedelics suppress anxiety,” said Alex Kwan, associate professor of biomedical engineering at Cornell University and lead author of the study, which appears in the journal Neuron“The idea is that if we know the neurobiology involved, we can design a better drug that would target these pathways.”

“This work provides insight into the cellular trigger for psychedelic-induced anxiety relief,” said Vidita Vaidya, senior professor of biological sciences at the Tata Institute of Fundamental Research in Mumbai, and corresponding author of the paper.

The pathway in the ventral hippocampus, a brain structure involved in social memory, emotion and affect, does not appear to cause the hallucinations that are a hallmark of DOI, suggesting that some of the therapeutic effects of psychedelics, including reductions in PTSD, depression and anxiety, may be isolated to discrete brain circuits, Vaidya said.

“This opens up the possibility of designing psychedelic-inspired drugs that target anxiety without causing powerful hallucinations,” she added.

In this study, the team tested rats and mice in a maze designed to study anxiety. The maze consists of two sections: an enclosed area with walls where the rodent can feel safe, and a completely exposed section that is elevated off the ground.

“As you might expect, the animal tends to spend a lot of time in the closed wing,” Kwan said. “It’s kind of a standard test to determine how anxious the animal is and how much exploration it’s going to have.”

Researchers can assess anxiety levels based on the time spent in each area.

In one experiment, the team injected DOI into the bloodstream before running the rodents through the maze. They then systematically injected DOI into four different brain areas, one at a time, and tested for changes in anxiety.

“Surprisingly enough, only one region – the ventral hippocampus – when we infused it with DOI, was able to retain the psychedelic effect of reducing anxiety,” Kwan said.

Electrical recordings of the brain were measured by co-author Antonio Fernandez-Ruiz, assistant professor of neurobiology and behavior and the Nancy and Peter Meinig Family Scholar in Life Sciences in the College of Arts and Sciences. These recordings identified that fast-spiking interneurons, which make up only 10 to 15 percent of cells in the ventral hippocampus, showed increased firing under the influence of DOI. Interneurons are known to silence other neurons, creating controls so that different types of nerve cells are not all excited at the same time.

The study builds on previous research that identified abnormal hyperactivity in the ventral hippocampus when an animal is anxious, particularly neurons that communicate with the amygdala, the main emotion processing center.

“There is some evidence that in the state of anxiety, these cells are active, and perhaps the drug works by silencing some of them,” Kwan said.

In future work, the researchers hope to investigate how the amygdala might be involved.

The study benefited from Kwan and Fernandez-Ruiz’s collaboration across campuses to measure brain electrical signals and an international collaboration with Vaidya’s team, which led many of the behavioral aspects of the study. Other co-authors included researchers from Yale University, Columbia University and the New York State Psychiatric Institute.