The psychedelic drug DOI activates certain brain neurons to relieve anxiety

In a new study published in NeuronResearchers have discovered how the little-known psychedelic drug DOI (2,5-dimethoxy-4-iodamphetamine) can reduce anxiety by activating a specific group of neurons in the brain. In experiments on mice and rats, the drug reduced anxiety-like behavior by stimulating a series of neurons in the ventral hippocampus – a region associated with emotions and memory. These results offer important insights into how psychedelics affect the brain and could influence future treatments for anxiety.

The researchers conducted this study to explore the neural mechanisms by which psychedelics reduce anxiety, drawing on existing research that has demonstrated the potential therapeutic effects of drugs such as LSD and psilocybin. While previous studies suggested 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 wanted to determine the precise brain regions and neural activity responsible for the drug's anxiety-reducing effects. This work is particularly relevant because anxiety disorders are common 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 involved in the regulation of mood disorders. The fact that psychedelics modulate this neurotransmitter system is really fascinating,” said study author Praachi Tiwari, a postdoctoral fellow at the Center for Psychedelics and Consciousness Research at Johns Hopkins University.

“There have been few studies attempting to understand the neural circuitry underlying the mechanism of action of psychedelics in certain 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 appears to be involved in triggering the hallucinogenic response of psychedelics), can influence anxiety-like behavior in humans, rodents, and if so, then what is the underlying neural circuitry that controls this behavioral response?”

To investigate how DOI affects anxiety-like behavior, researchers conducted experiments on rats and mice. They first injected the animals with DOI and then monitored their behavior using standard anxiety tests, such as the elevated plus-maze and open-field tests. These tests determine how much time animals spend in open, potentially anxiety-inducing spaces, which provides information about their anxiety levels. The animals that received DOI showed less anxiety-like behavior and spent more time in the open arms of the maze or in the middle of the open field, suggesting that the drug had a calming effect.

Next, Tiwari and her colleagues used various 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 is associated with 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, similar to systemic administration. This identified the ventral hippocampus as the central site of action of the drug.

The researchers wanted to go further and understand exactly which types of neurons in the ventral hippocampus are 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 rapidly increasing parvalbumin-positive interneurons. These interneurons are known to play a crucial role in controlling the activity of neighboring neurons by inhibiting their firing. In this case, activation of these inhibitory neurons by DOI likely calmed other neurons in the area, resulting in a reduction in anxiety.

In addition to these findings, the researchers examined the role of a specific serotonin receptor, the so-called serotonin 2A receptor, which is involved in the effects of many psychedelics. They discovered that this receptor is highly expressed in a specific type of neurons in the ventral hippocampus called fast-spiking interneurons. These interneurons play a key role in controlling the activity of other neurons in the area and help maintain balance in the brain's 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 with a drug called MDL100907, which specifically targets serotonin 2A receptors and prevents them from activating. When the receptors were blocked, DOI no longer had a calming effect on the animals, showing that these receptors are essential to the drug's ability to reduce anxiety.

Next, the researchers used a genetic technique to restore serotonin 2A receptors in mice that had been genetically modified. By injecting a virus carrying the necessary genetic material directly into the ventral hippocampus, they were able to specifically reactivate the 5-HT2A receptors in the rapidly increasing interneurons. When these receptors were restored, the calming effects of DOI also returned, 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 related 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 that is associated with psychedelic-induced hallucinations. This suggests that the brain circuits involved in reducing anxiety are different from those that cause hallucinations, raising the possibility that future drugs could be designed to combat anxiety without causing hallucinations.

“The key finding is that there appears to be a discrete neural circuit that is acutely involved in the psychedelic-induced decrease in anxiety-like behavior,” Tiwari said PsyPost. “This neural circuit does not appear to overlap with the circuits that may trigger the hallucinogenic response in rodents or even locomotion behavior. This enables a better understanding of how potential therapeutic drugs can be developed to target specific aspects of behavioral response and provides fundamental insights into how the brain works in relation to responses in fear-based task measures.”

Although the study provides valuable insights, it also has some limitations. On the one hand, the research was carried out on animal models, so it remains unclear how directly these findings can be transferred to humans. While the ventral hippocampus is involved in emotional processing in rodents, fear in humans is more complex and involves multiple brain regions. Additionally, the study only examined the acute effects of DOI, so it is unknown whether the drug's anti-anxiety effects persist with long-term use or how it might interact with chronic anxiety.

“We cannot rule out the possibility that there are other regions in the brain that act independently or in tandem with the ventral hippocampus and produce a decrease in the anxiety-like response during acute DOI action,” Tiwari noted. “Furthermore, we cannot comment on the behavioral consequences of a chronic DOI effect on anxiety-like behavior. These are open questions and require further investigation.”

Future research could examine whether the effects observed in this study are applicable to other psychedelics such as LSD and psilocybin, which may act on other serotonin receptors or brain regions. Additionally, researchers are interested in studying the potential for long-term therapeutic effects, particularly 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 medications.

“Psychedelics can prove to be a great tool for understanding neuronal function, particularly with regard to the serotonergic system,” Tiwari said. “If the questions are formulated with great consideration, this can be a very useful way to study specific conditions in the brain.”

The study, “Ventral hippocampal parvalbumin interneurons control the acute anxiolytic effect 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 and 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.