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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Treatment-resistant major depression: Rationale for NMDA receptors as targets and nitrous oxide as therapy.Front Psychiatry. 2015; 6: 172
- Toward an evidence-based, operational definition of treatment-resistant depression: When enough is enough.JAMA Psychiatry. 2017; 74: 9-10
- A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.Arch Gen Psychiatry. 2006; 63: 856-864
- Ketamine: A paradigm shift for depression research and treatment.Neuron. 2019; 101: 774-778
- Ketamine: NMDA receptors and beyond.J Neurosci. 2016; 36: 11158-11164
- Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines.Nat Commun. 2020; 11: 72
- Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses.Mol Psychiatry. 2021; 26: 3277-3291
- GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions.J Clin Invest:. 2020; 130: 1336-1349
- Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents.Neurobiol Dis. 2020; 134104669
- NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons.J Neurosci. 2007; 27: 11496-11500
- Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy.Proc Natl Acad Sci U S A. 2018; 115: E3007-E3016
- Neurobiology of the rapid-acting antidepressant effects of ketamine: Impact and opportunities.Biol Psychiatry. 2021; 90: 85-95
- NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.Nature. 2011; 475: 91-95
- Antidepressant drugs act by directly binding to TrkB neurotrophin receptors.Cell. 2021; 184: 1299-1313.e19
- Brain-derived neurotrophic factor signaling in depression and antidepressant action.Biol Psychiatry. 2021; 90: 128-136
- BDNF signaling in context: From synaptic regulation to psychiatric disorders.Cell. 2022; 185: 62-76
- mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.Science. 2010; 329: 959-964
- (2R,6R)-hydroxynorketamine exerts mGLu2 receptor-dependent antidepressant actions.Proc Natl Acad Sci U S A. 2019; 116: 6441-6450
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites.Nature. 2016; 533: 481-486
- Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin.Nat Med. 1998; 4: 460-463
- Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures.J Neurosci. 1998; 18: 9716-9726
- Nitrous oxide for treatment-resistant major depression: A proof-of-concept trial.Biol Psychiatry. 2015; 78: 10-18
- A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression.Sci Transl Med. 2021; 13eabe1376
- Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis.J Neurosci. 2010; 30: 16788-16795
- Nitrous oxide (laughing gas) facilitates excitability in rat hippocampal slices through γ-aminobutyric acid A receptor-mediated disinhibition.Anesthesiology. 2005; 102: 230-234
- Acute effects of ethanol on hippocampal long-term potentiation and long-term depression are mediated by different mechanisms.Neuroscience. 2005; 136: 509-517
- Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function.Neuropharmacology. 2014; 86: 273-281
- Inhibitors of cellular stress overcome acute effects of ethanol on hippocampal plasticity and learning.Neurobiol Dis. 2020; 141104875
- Acute suppression of spontaneous neurotransmission drives synaptic potentiation.J Neurosci. 2013; 33: 6990-7002
- Central nervous system effects of subdissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers.Clin Pharmacol Ther. 1995; 58: 165-173
- Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade.Front Mol Neurosci. 2014; 7: 94
- Quinoxalinediones: Potent competitive non-NMDA glutamate receptor antagonists.Science. 1988; 241: 701-703
- Targeting homeostatic synaptic plasticity for treatment of mood disorders.Neuron. 2020; 106: 715-726
- Anesthetic ketamine impairs rats’ recall of previous information: The nitric oxide synthase inhibitor N-nitro-L-arginine methylester antagonizes this ketamine-induced recognition memory deficit.Anesthesiology. 2011; 114: 1345-1353
- Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice.J Clin Invest. 2011; 121: 1846-1857
- Cyclotraxin-B, the first highly potent and selective TrkB inhibitor, has anxiolytic properties in mice.PLoS One. 2010; 5e9777
- mTOR and cancer: Insights into a complex relationship.Nat Rev Cancer. 2006; 6: 729-734
- Regulation of microtubule-dependent protein transport by the TSC2/mammalian target of rapamycin pathway.Cancer Res. 2006; 66: 5258-5269
- Advances in understanding the actions of nitrous oxide.Anesth Prog. 2007; 54: 9-18
- Potential pathways involved in the rapid antidepressant effects of nitrous oxide.Biol Psychiatry. 2015; 78: 2-4
- Characterization of the novel nitric oxide synthase inhibitor 7-nitro indazole and related indazoles: Antinociceptive and cardiovascular effects.Br J Pharmacol. 1993; 110: 219-224
- Efficacy of intravenous ketamine in adolescent treatment-resistant depression: A randomized midazolam-controlled trial.Am J Psychiatry. 2021; 178: 352-362
- Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins.Aging Cell. 2015; 14: 265-273
- Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin.Neuropsychopharmacology. 2020; 45: 990-997
- Isoflurane produces antidepressant effects and induces TrkB signaling in rodents.Sci Rep. 2017; 7: 7811
- Lack of antidepressant effects of burst-suppressing isoflurane anesthesia in adult male Wistar outbred rats subjected to chronic mild stress.PLoS One. 2020; 15e0235046
- Involvement of nitric oxide in nitrous oxide anxiolysis in the elevated plus-maze.Biochem Behav. 1994; 48: 689-692
- Repeated nitrous oxide exposure exerts antidepressant-like effects through neuronal nitric oxide synthase activation in the medial prefrontal cortex.Front Psychiatry. 2020; 11: 837
- Nitric oxide and hippocampal synaptic plasticity.Biochem Pharmacol. 1993; 46: 777-785
- NMDA receptors and metaplasticity: Mechanisms and possible roles in neuropsychiatric disorders.Neurosci Biobehav Rev. 2012; 36: 989-1000
- Cellular mechanisms underlying the antidepressant effects of ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.Biol Psychiatry. 2008; 63: 349-352
- The effectiveness, safety and tolerability of ketamine for depression in adolescents and older adults: A systematic review.J Psychiatr Res. 2021; 137: 232-241
- Glutamate receptor dysfunction and schizophrenia.Arch Gen Psychiatry. 1995; 52: 998-1007
- NMDA receptor hypofunction model of schizophrenia.J Psychiatr Res. 1999; 33: 523-533
- Age-specific neurotoxicity in the rat associated with NMDA receptor blockade: Potential relevance to schizophrenia?.Biol Psychiatry. 1995; 38: 788-796
- GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine.Elife. 2014; 3e03581
- Exploring nitrous oxide as treatment of mood disorders: Basic concepts.J Clin Psychopharmacol. 2018; 38: 144-148
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.
