ABSTRACT
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.
Key Words
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Article Info
Publication History
Accepted:
June 14,
2022
Received in revised form:
June 3,
2022
Received:
February 16,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
DISCLOSURES
CFZ serves on the Scientific Advisory Board of Sage Therapeutics and has equity in Sage Therapeutics. Sage Therapeutics did not fund this research. CRC is a consultant to Sage Therapeutics and has research sponsored by Sage Therapeutics. PN has filed for intellectual property protection for the use of nitrous oxide in TRMD and is founder of NitroBiomedcial LLC. All other authors report no biomedical financial interests or potential conflicts of interest.
AUTHOR CONTRIBUTIONS
YI, SJM, CRC, PN and CFZ conceived the experiments; YI and CFZ designed research and analyzed data; YI performed experiments; F-FH did measurements of N2O and CO2; CFZ wrote the paper and all authors edited and revised the paper.
Identification
Copyright
© 2022 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
