Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia.
Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
J Pharmacol Exp Ther. 2015 Jan;352(1):156-65. doi: 10.1124/jpet.114.218057. Epub 2014 Nov 3.
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.
氧化亚氮（N2O）气体是一种广泛应用于牙科和医学的麻醉辅助剂，也常被滥用。研究表明，N2O 会改变 N-甲基-D-天冬氨酸（NMDA）、GABAA、阿片类和 5-羟色胺（5-HT）受体等的功能。然而，N2O 与滥用相关的中枢神经系统效应的受体系统尚不清楚。本研究探讨了产生 N2O 辨别刺激效应的受体系统。接受过 10 分钟 60% N2O+40%氧气与 100%氧气暴露辨别训练的 B6SJLF1/J 雄性小鼠作为研究对象。高亲和力 NMDA 受体通道阻滞剂（+）-MK-801 马来酸盐[（5S，10R）-（+）-5-甲基-10,11-二氢-5H-二苯并[a，d]环庚烯-5,10-亚胺马来酸盐]和低亲和力阻滞剂美金刚部分模拟了 N2O 的刺激效应。竞争性 NMDA 拮抗剂 CGS-19755（顺式-4-[膦酸甲基]-哌啶-2-羧酸）和 NMDA 甘氨酸位点拮抗剂 L701-324 [7-氯-4-羟基-3-（3-苯氧基）苯基-2（1H）-喹啉酮]均未产生 N2O 样刺激效应。一系列 GABAA 激动剂和正调节剂，包括咪达唑仑、戊巴比妥、muscimol 和 gaboxadol（4,5,6,7-四氢异恶唑并[4,5-c]吡啶-3-醇），均未产生 N2O 样刺激效应。μ-、κ-和 δ-阿片类激动剂以及 5-羟色胺（5-HT）1B/2C（5-HT1B/2C）和 5-HT1A 激动剂也未产生 N2O 样刺激效应。乙醇部分替代了 N2O。（+）-MK-801 和乙醇预处理而非咪达唑仑预处理也显著增强了 N2O 的辨别刺激效应。我们的结果支持这样的假设，即 N2O 的辨别刺激效应至少部分是由 NMDA 拮抗剂作用介导的，类似于通道阻滞剂产生的作用。然而，由于测试的药物均未完全模拟 N2O 的刺激效应，因此可能还涉及其他机制。
