Serotoninergic psychedelics like psilocybin can produce lasting reductions in depressive symptoms, but their mechanism is unclear. In a mouse forced swim test model, the psychedelic DOI was tested for effects on behavior and 5-HT2A receptor levels in the medial prefrontal cortex. Mice exposed to swim stress developed passive coping behavior six days later, but this was not linked to increased head twitch responses or consistent changes in 5-HT2A receptor levels. A low dose of DOI (0.2 mg/kg) unexpectedly increased immobility, while a high dose (2 mg/kg) had no significant effect. DOI did cause a dose-dependent decrease in 5-HT2A levels in stressed mice. These results do not support the idea that downregulating 5-HT2A receptors in the medial prefrontal cortex underlies antidepressant-like effects of serotoninergic psychedelics.
Activating the serotonin-2A receptor can produce antidepressant effects, but also risks hallucinations. Recent work suggests that using weak partial agonists or very low doses might separate these effects. Computer simulations of the receptor bound to different drugs show that modest activation may yield only antidepressant benefits, while excessive activation causes hallucinations. This finding points to a possible drug development strategy: administering a sufficiently weak partial agonist could provide therapeutic effects without hallucinogenic side effects, avoiding the abuse and narrow dosing problems of microdosing.
The serotonin-2A receptor (5-HT2AR) is a target for antidepressants that could work quickly or in treatment-resistant cases, but activating it can cause hallucinations. Recent research suggests certain partial agonists might produce antidepressant effects without hallucinations, though the molecular details are unclear. This study used molecular dynamics simulations of the receptor bound to two antipsychotics, three potential non-hallucinogens, and two hallucinogens. Findings suggest modest receptor activation yields only antidepressant effects, while hallucinations result from excessive activation. Modest activation via a sufficiently weak partial agonist may offer a viable drug development pathway, whereas microdosing may be problematic due to abuse potential and narrow therapeutic windows.
Activation of the serotonin 2A (5-HT2A) receptor suppresses fear expression but does not affect retention of fear extinction. Using the psychedelic DOI in mice, the authors found that 5-HT2A receptor activation reduced anxiety-like avoidance behavior and diminished fear expression in multiple tasks, including passive avoidance and auditory fear conditioning. The effect depended on 5-HT2A receptors in the amygdala: local infusion of a 5-HT2A antagonist into the amygdala reversed the effect, while local DOI infusion into the amygdala was sufficient to suppress fear expression. These findings clarify a neural mechanism by which psychedelics may reduce fear, but provide no evidence that they enhance fear extinction memory.