Nitrous Oxide, a Rapid Antidepressant, Has Ketamine-like Effects on Excitatory Transmission in Adult Hippocampus

Background: Nitrous oxide (N2O) is a non-competitive inhibitor of NMDA receptors (NMDARs) that appears to have ketamine-like rapid antidepressant effects in patients with treatment resistant major depression. In preclinical studies, ketamine enhances glutamate-mediated synaptic transmission in hippocampus and prefrontal cortex. The present study examined effects of N2O on glutamate transmission in hippocampus, and compared its effects to ketamine.

Methods: Glutamate-mediated synaptic transmission was studied in the CA1 region of hippocampal slices from adult albino rats using standard extracellular recording methods. Effects of N2O and ketamine at sub-anesthetic concentrations were evaluated by acute administration.

Results: Akin to 1 μM ketamine, 30% N2O administered for 15-20 min resulted in persistent enhancement of synaptic responses mediated by both AMPA receptors (AMPARs) and NMDARs. Synaptic enhancement by both N2O and ketamine was blocked by co-administration of a competitive NMDAR antagonist at saturating concentration, but only ketamine was blocked by an AMPAR antagonist. Synaptic enhancement by both agents involved tropomyosin receptor kinase B (TrkB), mechanistic target of rapamycin (mTOR), and nitric oxide synthase (NOS), with some differences between N2O and ketamine. N2O potentiation occluded enhancement by ketamine, and in vivo N2O exposure occluded further potentiation by both N2O and ketamine.

Conclusions: These results indicate that N2O has ketamine-like effects on hippocampal synaptic function at a sub-anesthetic, but therapeutically relevant concentration. These two rapid antidepressants have similar, but not identical mechanisms that result in persisting synaptic enhancement, possibly contributing to psychotropic actions.