TY - JOUR
T1 - Nitrous Oxide, a Rapid Antidepressant, Has Ketamine-like Effects on Excitatory Transmission in the Adult Hippocampus
AU - Izumi, Yukitoshi
AU - Hsu, Fong Fu
AU - Conway, Charles R.
AU - Nagele, Peter
AU - Mennerick, Steven J.
AU - Zorumski, Charles F.
N1 - Funding Information:
This work was supported by the National Institute of Mental Health (Grant Nos. MH101874 [to SJM and CFZ], MH114866 [to CFZ], MH123748 [to SJM ], MH122379 [to CFZ and SJM ]); the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences (Grant Nos. P30DK020579, P30DK056341, and P41GM103422 [to F-FH]); the Taylor Family Institute for Innovative Psychiatric Research ; and the Bantly Foundation .
Funding Information:
This work was supported by the National Institute of Mental Health (Grant Nos. MH101874 [to SJM and CFZ], MH114866 [to CFZ], MH123748 [to SJM], MH122379 [to CFZ and SJM]); the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences (Grant Nos. P30DK020579, P30DK056341, and P41GM103422 [to F-FH]); the Taylor Family Institute for Innovative Psychiatric Research; and the Bantly Foundation. We thank Kazuko Izumi and Ann Benz for technical assistance and members of the Taylor Family Institute for helpful comments and advice. YI, SJM, CRC, PN, and CFZ conceived the experiments; YI and CFZ designed the research and analyzed the data; YI performed the experiments; F-FH did measurements of N2O and CO2; CFZ wrote the article, and all authors edited and revised the article. 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 NitroBiomedical, LLC. All other authors report no biomedical financial interests or potential conflicts of interest.
Publisher Copyright:
© 2022 Society of Biological Psychiatry
PY - 2022/12/15
Y1 - 2022/12/15
N2 - 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.
AB - 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.
KW - Laughing gas
KW - NMDA receptors
KW - Nitric oxide synthase
KW - TrkB receptors
KW - mTOR
UR - http://www.scopus.com/inward/record.url?scp=85137097032&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2022.06.016
DO - 10.1016/j.biopsych.2022.06.016
M3 - Article
C2 - 36050137
AN - SCOPUS:85137097032
SN - 0006-3223
VL - 92
SP - 964
EP - 972
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 12
ER -