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 durably activates a specific population of neurons in the cingulate cortex of rodents exposed to chronic stress. This activation rescues a stress-induced hypoactivity state in layer V (L5) pyramidal neurons and is necessary for N2O's antidepressant-like effects. Although N2O is believed to work primarily by blocking NMDA receptors, L5 neurons still activate when NMDA receptor function is inhibited. Instead, N2O inhibits calcium-sensitive potassium (SK2) channels, driving L5 neuron activity and antidepressant-like effects. These findings identify a novel molecular and circuit mechanism for N2O's fast antidepressant action.