Psychedelic drug DOI activates specific brain neurons to ease anxiety

In a new study published in Neuron, researchers at the Tata Institute of Fundamental Research in India uncovered how the little-known psychedelic drug DOI (2,5-dimethoxy-4-iodoamphetamine) can reduce anxiety by activating a specific group of neurons in the brain. In experiments conducted on mice and rats, the drug reduced anxiety-like behaviors by stimulating a set of neurons in the ventral hippocampus—a region associated with emotion and memory. These findings offer key insights into how psychedelics might influence the brain and could inform future treatments for anxiety.

The researchers conducted this study to explore the neural mechanisms through which psychedelics reduce anxiety, building on existing research that has shown the potential therapeutic effects of drugs like LSD and psilocybin. While previous studies indicated that serotonergic psychedelics could reduce anxiety, the specific brain circuits involved had not been clearly identified.

By focusing on DOI, a psychedelic known to bind strongly to serotonin receptors, the researchers aimed to pinpoint the exact brain regions and neuronal activity responsible for the drug’s anxiety-reducing effects. This work is particularly relevant because anxiety disorders are widespread and often difficult to treat, and understanding how psychedelics interact with the brain could lead to more effective therapies.

“The serotonergic system is known to be implicated in the regulation of mood-related disorders. The fact that psychedelics modulate this neurotransmitter system is really intriguing,” said study author Praachi Tiwari, who is now a postdoctoral researcher at the Center for Psychedelics and Consciousness Research at Johns Hopkins University.

“There were hardly any studies that tried to understand the neural circuit underlying the mechanism of action of psychedelics in specific neuropsychiatric disorders. This piqued our interest, and we wanted to specifically understand whether the serotonergic psychedelic DOI, which has a high affinity for the serotonin-2A receptor (which seems to be involved in driving the hallucinogenic response of psychedelics), can affect anxiety-like behavior in rodents, and if so, then what is the underlying neural circuit through which this behavioral response is driven.”

To investigate how DOI affects anxiety-like behavior, the researchers conducted experiments on rats and mice. They first injected DOI into the animals and then observed their behavior using standard tests for anxiety, such as the elevated plus maze and open field test. These tests assess how much time the animals spend in open, potentially anxiety-inducing spaces, which provides an indication of their anxiety levels. The animals that received DOI showed reduced anxiety-like behavior, spending more time in the open arms of the maze or in the center of the open field, suggesting that the drug had a calming effect.

Next, Tiwari and her colleagues used a variety of techniques to understand the neural activity behind these behavioral changes. They specifically targeted the ventral hippocampus, a brain region that plays a key role in processing emotions and has been implicated in anxiety. To confirm the involvement of this brain region, they injected DOI directly into the ventral hippocampus and found that it reduced anxiety in the animals, much like when it was administered systemically. This pinpointed the ventral hippocampus as a key site of action for the drug.

The researchers wanted to go further and understand exactly which types of neurons in the ventral hippocampus were responsible for the drug’s effects. Using sophisticated methods, including electrophysiology and optogenetics, they found that DOI primarily activates a specific group of neurons called fast-spiking parvalbumin-positive interneurons. These interneurons are known to play a crucial role in controlling the activity of nearby neurons by inhibiting their firing. In this case, the activation of these inhibitory neurons by DOI likely quieted other neurons in the area, leading to reduced anxiety.

In addition to these findings, the researchers explored the role of a specific serotonin receptor, known as the serotonin-2A receptor, which is involved in the effects of many psychedelics. They discovered that this receptor is highly expressed in a particular type of neuron in the ventral hippocampus called fast-spiking interneurons. These interneurons play a key role in controlling the activity of other neurons in the region, helping to maintain balance in brain circuits.

To confirm the involvement of 5-HT2A receptors in the anxiety-reducing effects of DOI, the researchers used a two-part approach. First, they selectively blocked these receptors using a drug called MDL100907, which specifically targets and prevents serotonin-2A receptors from being activated. When the receptors were blocked, DOI no longer had its calming effect on the animals, showing that these receptors are essential for the drug’s ability to reduce anxiety.

Next, the researchers used a genetic technique to restore the serotonin-2A receptors in mice that had been genetically modified to lack them. By injecting a virus carrying the necessary genetic material directly into the ventral hippocampus, they were able to reactivate the 5-HT2A receptors specifically in the fast-spiking interneurons. When these receptors were restored, the calming effects of DOI were also reinstated, further proving the crucial role of these receptors in reducing anxiety.

One of the most intriguing aspects of the study is that the DOI-induced reduction in anxiety does not appear to be linked to the hallucinogenic effects often associated with psychedelics. Tiwari and her colleagues found that while DOI activated neurons in the ventral hippocampus, it did not trigger the head-twitch response, a behavioral marker in rodents associated with psychedelic-induced hallucinations. This suggests that the brain circuits involved in reducing anxiety are distinct from those that cause hallucinations, raising the possibility that future drugs could be designed to target anxiety without causing hallucinations.

“The main finding is that there seems to be a discrete neural circuit involved in the psychedelic-evoked decline in anxiety-like behavior acutely,” Tiwari told PsyPost. “This neural circuit does not seemingly overlap with the circuits that potentially drive the hallucinogenic-like response in rodents, or even the locomotion-related behavior. This allows for a better understanding of how potential therapeutic drugs can be designed to target specific aspects of behavioral response and gives fundamental insights into the functioning of the brain with respect to responses in anxiety-based task measures.”

Although the study provides valuable insights, it also has some limitations. For one, the research was conducted on animal models, so it remains unclear how directly these findings will translate to humans. While the ventral hippocampus in rodents is involved in emotional processing, human anxiety is more complex and involves multiple brain regions. Additionally, the study only looked at the acute effects of DOI, so it is unknown whether the drug’s anti-anxiety effects would persist with long-term use or how it might interact with chronic anxiety conditions.

“We cannot preclude the possibility that there may be other regions in the brain that act independently or in tandem with the ventral hippocampus to evoke a decline in anxiety-like response upon acute DOI action,” Tiwari noted. “We also cannot comment on the behavioral consequence of chronic DOI action on anxiety-like behavior. These are open questions, and need further investigation.”

Future research could explore whether the effects observed in this study are applicable to other psychedelics, such as LSD and psilocybin, which may act on different serotonin receptors or brain regions. Moreover, researchers are keen to investigate the potential for long-term therapeutic effects, especially in individuals with stress-related anxiety disorders.

Understanding how these drugs work in the brain could pave the way for developing new treatments that target specific neural circuits to reduce anxiety without the side effects associated with current therapies or psychedelic drugs.

“Psychedelics can prove to be a great tool to understand neural function, especially with respect to the serotonergic system,” Tiwari said. “If the questions are designed with great deliberation, it can be a very useful way to study specific states in the brain.”

The study, “Ventral hippocampal parvalbumin interneurons gate the acute anxiolytic action of the serotonergic psychedelic DOI,” was authored by Praachi Tiwari, Pasha A. Davoudian, Darshana Kapri, Ratna Mahathi Vuruputuri, Lindsay A. Karaba, Mukund Sharma, Giulia Zanni, Angarika Balakrishnan, Pratik R. Chaudhari, Amartya Pradhan, Shital Suryavanshi, Kevin G. Bath, Mark S. Ansorge, Antonio Fernandez-Ruiz, Alex C. Kwan, and Vidita A. Vaidya.