Nitrous Oxide, a Rapid Antidepressant, Has Ketamine-like Effects on Excitatory Transmission in Adult Hippocampus
Biological Psychiatry June 1, 2022 Y. Izumi, F. Hsu, C. Conway et al.
Nitrous oxide (N2O), like ketamine, produces lasting enhancement of glutamate-mediated synaptic transmission in the hippocampus. In rat hippocampal slices, 30% N2O administered for 15-20 minutes persistently strengthened responses mediated by both AMPA and NMDA receptors, an effect blocked by a competitive NMDA receptor antagonist but not by an AMPA receptor antagonist, unlike ketamine. Both agents required TrkB, mTOR, and nitric oxide synthase, though with some mechanistic differences. N2O potentiation occluded enhancement by ketamine, and prior in vivo N2O exposure prevented further potentiation by either agent. These findings suggest N2O has ketamine-like effects on hippocampal synaptic function at a sub-anesthetic, therapeutically relevant concentration.