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.
Ketamine, a fast-acting antidepressant, works in part by blocking a signaling pathway between immune cells and neurons in the brain. In mice with depression-like symptoms caused by corticosterone, a single dose of ketamine (10 mg/kg) reversed behavioral deficits, reduced inflammation, and restored the structure of brain cells. Blocking the CX3CL1/CX3CR1 signaling pathway—either with a drug or by silencing the gene—eliminated both the behavioral and brain-cell benefits of ketamine. This suggests that this chemokine pathway is essential for ketamine's antidepressant effects and could be a new target for treating depression.