Ketamine produces rapid antidepressant-like effects in mice within 60 minutes and increases brain serotonin levels. The sustained effects at 24 hours require an intact serotonin system: depleting serotonin or knocking out the serotonin synthesis enzyme Tph2 eliminated the 24-hour but not the 60-minute effects. Blocking AMPA receptors with NBQX also prevented the rise in serotonin and abolished the sustained antidepressant-like effects. Serotonergic neurotransmission is necessary for ketamine's lasting antidepressant action, and this mechanism involves AMPA receptors.
Psilocybin rapidly reversed depressive-like behaviors in mice subjected to chronic restraint stress, an effect comparable to ketamine. Both drugs prevented stress-induced loss of astrocytes and reduced levels of the A1 astrocyte marker C3 protein in the prefrontal cortex. The active metabolite psilocin stimulated primary astrocyte activation, proliferation, and release of ATP, lactate, and glutamate, and improved mitochondrial function. Psilocin also reversed impairments caused by A1 astrocytes. Depleting astrocytes in the prelimbic region of the medial prefrontal cortex diminished psilocybin's antidepressant action in unstressed mice, suggesting astrocytes play a key role in the drug's effects.