Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, P.O. Box 980613, Richmond, VA 23298-0613, USA.
Psychopharmacology (Berl). 2010 Dec;212(4):559-69. doi: 10.1007/s00213-010-1979-4. Epub 2010 Aug 10.
Several neurotransmitter systems have been hypothesized to be involved in the in vivo effects of volatile anesthetics. Drug discrimination may represent a novel procedure to explore the neurochemical systems underlying the sub-anesthetic behavioral effects of these compounds.
The purpose of the present study was to examine the contribution of GABA(A) and NMDA receptors to the discriminative stimulus effects of a behaviorally active sub-anesthetic concentration of isoflurane vapor.
Sixteen B6SJLF1/J mice were trained to discriminate 10 min of exposure to 6,000 ppm isoflurane vapor from air. Substitution tests were conducted with volatile anesthetics, abused vapors, GABA(A) positive modulators, NMDA antagonists, and nitrous oxide.
The volatile anesthetics, enflurane and halothane as well as the abused vapors toluene and 1,1,1-trichloroethane fully substituted for isoflurane. The GABA(A) positive modulators, pentobarbital, midazolam, and zaleplon but not the direct GABA(A) agonist, muscimol, produced high levels of partial substitution for isoflurane. The anticonvulsant, valproic acid fully substituted for isoflurane but a second, tiagabine, did not substitute. The competitive NMDA antagonist, CGS-19755, fully and the non-competitive NMDA antagonist, dizocilpine, partially substituted for isoflurane. The glycine-site NMDA antagonist, L-701,324 did not substitute for isoflurane. Gamma-hydroxybutric acid and nitrous oxide gas also failed to substitute for isoflurane.
The discriminative stimulus effects of sub-anesthetic concentrations of isoflurane vapor are shared by other vapor anesthetics and abused inhalants. The discriminative stimulus effects of isoflurane vapor appear to be mediated by both positive allosteric modulation of GABA(A) receptors as well as antagonism of NMDA receptors.
有几种神经递质系统被假设参与了挥发性麻醉剂在体内的作用。药物辨别可能代表一种新的程序，以探索这些化合物的亚麻醉行为效应背后的神经化学系统。
本研究的目的是检查 GABA(A) 和 NMDA 受体对行为活性亚麻醉浓度异氟烷蒸气的辨别刺激效应的贡献。
16 只 B6SJLF1/J 小鼠接受训练以辨别 10 分钟暴露于 6000 ppm 异氟烷蒸气与空气。用挥发性麻醉剂、滥用蒸气、GABA(A) 正变构调节剂、NMDA 拮抗剂和一氧化二氮进行替代测试。
挥发性麻醉剂恩氟烷和氟烷以及滥用蒸气甲苯和 1,1,1-三氯乙烷完全替代了异氟烷。GABA(A) 正变构调节剂戊巴比妥、咪达唑仑和扎来普隆，但不是直接的 GABA(A) 激动剂，muscimol，产生了高水平的异氟烷部分替代。抗惊厥药丙戊酸完全替代了异氟烷，但另一种，tiagabine，没有替代。竞争性 NMDA 拮抗剂 CGS-19755 完全替代了异氟烷，而非竞争性 NMDA 拮抗剂 dizocilpine 部分替代了异氟烷。甘氨酸位 NMDA 拮抗剂 L-701,324 没有替代异氟烷。γ-羟基丁酸和一氧化二氮气体也未能替代异氟烷。
亚麻醉浓度异氟烷蒸气的辨别刺激效应与其他蒸气麻醉剂和滥用吸入剂共享。异氟烷蒸气的辨别刺激效应似乎是由 GABA(A) 受体的正变构调节以及 NMDA 受体的拮抗作用介导的。
