N-methyl-D-aspartate receptor channel blocker-like discriminative stimulus effects of nitrous oxide gas.

Article date: 2015/1/20

PubMed ID: 1319602

Journal name: The Journal of pharmacology and experimental therapeutics (ISSN: 1521-0103)

DOI: 10.1124/jpet.114.218057


Nitrous oxide (N2O) gas is a widely used anesthetic adjunct in dentistry and medicine that is also commonly abused. Studies have shown that N2O alters the function of the N-methyl-d-aspartate (NMDA), GABAA, opioid, and serotonin receptors among others. However, the receptors systems underlying the abuse-related central nervous system effects of N2O are unclear. The present study explores the receptor systems responsible for producing the discriminative stimulus effects of N2O. B6SJLF1/J male mice trained to discriminate 10 minutes of exposure to 60% N2O + 40% oxygen versus 100% oxygen served as subjects. Both the high-affinity NMDA receptor channel blocker (+)-MK-801 maleate [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] and the low-affinity blocker memantine partially mimicked the stimulus effects of N2O. Neither the competitive NMDA antagonist, CGS-19755 (cis-4-[phosphomethyl]-piperidine-2-carboxylic acid), nor the NMDA glycine-site antagonist, L701-324 [7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolinone], produced N2O-like stimulus effects. A range of GABAA agonists and positive modulators, including midazolam, pentobarbital, muscimol, and gaboxadol (4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol), all failed to produce N2O-like stimulus effects. The μ-, κ-, and δ-opioid agonists, as well as 5-hydroxytryptamine (serotonin) 1B/2C (5-HT1B/2C) and 5-HT1A agonists, also failed to produce N2O-like stimulus effects. Ethanol partially substituted for N2O. Both (+)-MK-801 and ethanol but not midazolam pretreatment also significantly enhanced the discriminative stimulus effects of N2O. Our results support the hypothesis that the discriminative stimulus effects of N2O are at least partially mediated by NMDA antagonist effects similar to those produced by channel blockers. However, as none of the drugs tested fully mimicked the stimulus effects of N2O, other mechanisms may also be involved.

Author List: Richardson Kellianne J, Shelton Keith L

Publication Types: Journal Article; Research Support, N.I.H., Extramural

Article Date: 2014/11/03

Substances mentioned in the article: Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, Serotonin; Toluene; Nitrous Oxide;

Mesh terms: Animals; Male; Mice; Nitrous Oxide/pharmacology; Receptors, GABA-A/metabolism; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors; Receptors, Opioid/metabolism; Receptors, Serotonin/metabolism; Toluene/pharmacology;

Citations: - 21836460

1319602.txt · Last modified: 2018/11/20 14:25 (external edit)