4-OH-DiPT, a fast-acting and shorter-lasting derivative of psilocybin, reduces learned fear responses in mice by enhancing inhibitory signaling in the brain. It activates 5-HT2A receptors on interneurons in the basolateral amygdala, increasing GABAergic inhibition of principal neurons. In female mice, 4-OH-DiPT before extinction training reduced freezing to conditioned cues and later decreased avoidance behaviors in several tests, while male mice showed no significant differences. The compound acts as a near full agonist at 5-HT2A receptors and has comparable activity at mouse and human 5-HT2A/2B/2C receptors. These findings suggest a potential mechanism for suppressing learned fear.
A single subanesthetic dose of esketamine (30 mg/kg) alleviated PTSD-like symptoms in mice exposed to electric foot shocks. The medial prefrontal cortex showed increased numbers of Iba1-positive microglial cells and elevated pro-inflammatory cytokines (IL-6, TNF-α), indicating neuroinflammation, along with increased expression of myelin-related proteins (MBP, MAG, Olig2, PDGFRα), suggesting abnormal myelination. Esketamine treatment suppressed both the neuroinflammatory response and the aberrant myelination. The findings suggest that neuroinflammation and abnormal myelination contribute to PTSD development and highlight esketamine's therapeutic potential.