New research indicates that the development of new drugs based on psychedelics may provide a way to separate treatment from hallucinogenic effects. A study published in Science suggests that the anti-anxiety and hallucination-inducing properties of psychedelic drugs act through different neural circuits in a mouse model. Researchers found that decoupling the positive effects of psychedelics from their hallucinogenic effects is not just about designing new chemical compounds, but also involves targeting specific neural circuits. The study validates the importance of identifying circuits responsible for the effects of psychedelics.
To measure anti-anxiety behaviors in mice, researchers conducted tests using two models: the elevated plus maze and the marble burying test. Mice were placed in an elevated maze with open and closed arms, and those displaying anxiety tended to stay in the closed arms. In the marble burying test, anxious mice tended to bury marbles compulsively. The study found that psychedelics like 2,5-dimethoxy-4-iodoamphetamine (DOI) reduced marble burying and increased exploratory behavior in mice, while also inducing hallucinations. By identifying the neurons activated by DOI responsible for reducing anxiety, researchers aimed to reactivate them to mimic anti-anxiety effects without hallucinogenic side effects.
Using a molecular tagging tool called scFLARE2, researchers highlighted the neurons activated by DOI in the medial prefrontal cortex to isolate a psychedelic responsive network involved in reducing anxious behavior. Optogenetics, or light stimulation, was then used to reactivate these specific neurons, resulting in a reduction of anxiety-like behaviors in mice. Further genetic profiling of the neuron types revealed that activating some neurons led to downstream changes, affecting behavioral outcomes beyond receptor activation. The study emphasizes how targeting specific neural circuits can have broader effects on the brain network, potentially leading to therapeutic benefits.
While the study focused on dissecting the basic circuit mechanisms of psychedelics rather than developing therapeutic drugs, the findings shed light on the potential for targeted therapeutics with improved safety profiles. Understanding how psychedelics affect the brain at the neural circuit level is a primary goal of the Institute for Psychedelics and Neurotherapeutics. By identifying the neural circuits activated by psychedelics, researchers aim to pave the way for the development of new drugs that can provide therapeutic benefits without the hallucinogenic effects typically associated with psychedelics.
The research was spearheaded by postdoctoral researcher Jessie Muir and junior specialist Sophia Lin, with additional contributions from other team members. Funding for the study was provided by various organizations, including the Burroughs Wellcome Fund, Brain & Behavior Research Foundation, National Institutes of Health, and others. By unraveling the mechanisms through which psychedelics affect the brain, researchers hope to lay the groundwork for the development of targeted therapeutics that can harness the benefits of psychedelics while minimizing unwanted side effects.