Abstract:
Stress pervades modern life. It affects various brain functions, posing risks for many psychiatric disorders. However, few therapeutics are available to combat such deleterious effects of stress. One class of candidate drugs are psychedelics. With potent and fascinating effects on the human mind, these drugs have received renewed research interest in recent years. However, their hallucinogenic effects remain a concern for clinical applications. Using a mouse model of unpredictable mild stress, we investigated a novel compound called tabernanthalog (TBG), which is similar in structure to the psychedelic drug ibogaine but free from its hallucinogenic and toxic effects. We found that a single low dose of TBG can correct stress-induced behavioral deficits including anxiety, cognitive inflexibility, and defective sensory processing. In the stressed brain, TBG promotes the regrowth of stress-disrupted connections between cortical neurons and normalizes their activity patterns. Our study highlights the potential of using analogs of psychedelics to treat stress-related brain disorders and provides novel insights into the neural mechanisms underlying their therapeutic effects.