The hallucinogen 5-MeO-DMT reduces low-frequency cortical oscillations (<4 Hz) in the prefrontal cortex, visual cortex, somatosensory cortex, and auditory cortex of anesthetized mice. In the prefrontal cortex, this reduction occurs via 5-HT(1A) receptors, as it persists in 5-HT(2A) receptor knockout mice and is blocked by a 5-HT(1A) antagonist. In sensory areas, the effect in visual cortex also involves 5-HT(1A) receptors, while other regions require 5-HT(2A) receptors. Antipsychotic drugs reverse these disruptions, supporting the model's use for developing new treatments.
Depression involves disruptions in the endoplasmic reticulum (ER) of serotonin neurons. In mice, artificially inducing ER stress in these neurons reduced Egr1-dependent serotonin activity and neurotransmission, leading to impaired neuroplasticity in forebrain regions and depressive-like behaviors. Ketamine reversed these effects by activating eIF2α signaling, which rapidly restored neuroplasticity. The findings identify ER stress in serotonin neurons as a cellular mechanism in depression and highlight eIF2α as a key target for ketamine's fast antidepressant action.