Abstract
Background
Nitrous oxide (N2O) is a noncompetitive inhibitor of NMDA receptors 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 the hippocampus and prefrontal cortex. In this study, we examined the effects of
N2O on glutamate transmission in the hippocampus and compared its effects to those of
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 subanesthetic concentrations were evaluated by acute administration.
Results
Akin to 1 μM ketamine, 30% N2O administered for 15–20 minutes resulted in persistent enhancement of synaptic responses
mediated by both AMPA receptors and NMDA receptors. Synaptic enhancement by both N2O and ketamine was blocked by co-administration of a competitive NMDA receptor antagonist
at saturating concentration, but only ketamine was blocked by an AMPA receptor antagonist.
Synaptic enhancement by both agents involved TrkB (tropomyosin receptor kinase B),
mTOR (mechanistic target of rapamycin), and NOS (nitric oxide synthase) 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 subanesthetic, but
therapeutically relevant concentration. These 2 rapid antidepressants have similar,
but not identical mechanisms that result in persisting synaptic enhancement, possibly
contributing to psychotropic actions.
Keywords
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Article Info
Publication History
Published online: June 22, 2022
Accepted:
June 14,
2022
Received in revised form:
June 3,
2022
Received:
February 16,
2022
Identification
Copyright
© 2022 Society of Biological Psychiatry.
