A single injection of ketamine (15 mg/kg) in mice with chronic neuropathic pain temporarily reduced mechanical hypersensitivity for less than 24 hours, but its antidepressant effect lasted at least 72 hours. Ketamine also normalized the expression of MKP-1 and phosphorylation of ERK in the anterior cingulate cortex, molecular changes that may underlie its therapeutic effects on pain-induced depression.
The antidepressant effects of NMDA receptor blockers like ketamine and nitrous oxide (laughing gas) become apparent only after their acute psychoactive effects wear off. In mice, nitrous oxide exposure initially increased markers of neuronal excitability, but regulation of the BDNF receptor TrkB and GSK3β signaling occurred gradually after drug discontinuation, during a brain state dominated by slow EEG activity. Subanesthetic ketamine and seizure-inducing flurothyl also produced slow oscillations after their acute effects subsided. A sedative that directly induces slow oscillations did not increase neuronal excitability markers or produce antidepressant-like behavior, suggesting that transient cortical excitability followed by homeostatic slow oscillations and TrkB-GSK3β signaling are critical for rapid antidepressant responses.