Ketamine's rapid antidepressant effects in chronically stressed male mice require wakefulness. When the anesthetic isoflurane was coadministered at either sedative or general anesthetic doses, ketamine no longer produced dissociative-like behaviors or distinct neuronal activity patterns in prefrontal cortex pyramidal neurons, and antidepressant-like behavioral responses and the molecular plasticity marker c-Fos failed to appear 24 hours later. These results indicate that suppressing psychedelic-induced experiences by altering consciousness may impair activity-dependent plasticity mechanisms necessary for ketamine's therapeutic actions.
A single dose of inhaled nitrous oxide (N2O) rapidly and specifically activates layer V (L5) pyramidal neurons in the prefrontal cortex of rodents exposed to chronic stress. This activation reverses a stress-linked hypoactivity state, persists after N2O exposure, and is necessary for the antidepressant effect. The activation occurs independently of NMDA-receptor function and synaptic activity, contrary to N2O's purported mechanism. Instead, N2O inhibits calcium-sensitive potassium (SK2) channels, driving both rapid and sustained L5 activity and antidepressant-like effects. The findings suggest a novel molecular target for fast-acting antidepressants.