The mechanisms of anesthetic abuse

麻醉滥用的机制

• 批准号: 13671622
• 负责人: NAKAO Shinichi
• 金额: $ 2.11万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671622/
• 关键词: Nucleus accumbens; Dopamine; Drug Abuse; Posterior cingulate and retrosplenial cortices; Ketamine; Nitrous Oxide; Xenon; Sigma 1 receptor; IP3受容体; プロポフォール; プラジキニン; シグマ受容体; ドロペリドール; デクスメデトミジン; 非競合性NMDA受容体拮抗薬

I have investigated the effects of various anesthetics on dopamine release in the rat nucleus accumbens(Ncs), which is closely related to drug addiction and psychotomimetic activity of drugs, and c-Fos expression in the rat posterior cingulate and retrosplenial cortices(PC/RS), which are considered to represent psychotomimetic activity of NMDA receptor antagonists. I have also studied the effects of several intravenous anesthetics on sigma 1 receptors, which have various CNS effects including drug addiction.Ketamine and nitrous oxide increased dopamine release in the Nac but xenon tended to decrease it. Repetitive administration of ketamine and nitrous oxide for 5 days did not further increase the dopamine release. Pentobarbital decreased the dopamine release and inhibited the ketamine-induced increase in dopamine release. Ketamine and nitrous oxide induced marked c-Fos expression in the PC/RS but xenon did not induce it. Nitrous oxide augmented the ketamine-induced c-Fos expression but xenon inhibited it. Clinically relevant doses of propofol affected sigma 1 receptor by a receptor binding assay, indicating that various CNS effects, such as drug addiction, psychotic activity, neuroprotection and anti-emetic activity, by propofol may be mediated, at least partly, by sigma 1 receptors.

本论文研究了不同麻醉剂对大鼠中脑核（Ncs）多巴胺释放和c-Fos表达的影响，前者与药物成瘾和药物拟精神病活性密切相关，后者被认为是NMDA受体拮抗剂拟精神病活性的代表。我还研究了几种静脉麻醉剂对sigma 1受体的影响，这些受体具有各种CNS效应，包括药物成瘾。氯胺酮和一氧化二氮增加了Nac中多巴胺的释放，但氙倾向于减少它。重复给予氯胺酮和一氧化二氮5天并没有进一步增加多巴胺的释放。戊巴比妥减少多巴胺释放，抑制氯胺酮引起的多巴胺释放增加。氯胺酮和一氧化二氮可诱导PC/RS中c-Fos表达，而氙则不诱导，一氧化二氮可增强氯胺酮诱导的c-Fos表达，氙则抑制c-Fos表达，临床相关剂量的异丙酚可通过受体结合试验影响sigma 1受体，表明异丙酚可能介导多种CNS效应，如药物成瘾、精神病活动、神经保护和止吐作用，至少部分是通过σ 1受体。

项目成果

Atsushi Nagata: "Xenon Inhibits but N2O Enhances Ketamine-Induced c-Fos Expression in the Rat Posterior Cingulate and Retrosplenial Cortices"Anesthesia & Analgesia. 92. 362-368 (2001)

Atsushi Nagata：“氙会抑制但 N2O 会增强氯胺酮诱导的大鼠后扣带皮层和脾后皮质中的 c-Fos 表达”麻醉

Shinichi Nakao: "Ketamine-induced c-Fos expression in the mouse posterior cingulate and retrosplenial cortices is mediated not only via NMDA receptors but also via sigma receptors"Brain Research. 926. 191-196 (2002)

Shinichi Nakao：“氯胺酮诱导的小鼠后扣带皮层和压后皮质中的 c-Fos 表达不仅通过 NMDA 受体介导，还通过 sigma 受体介导”《大脑研究》。

Shinich Nakao: "The inhibitory effect of propofol on ketamine-induced c-Fos expression in the posterior cingulate and retrosplenial cortices is mediated by GABAA receptor activation"Acta Anaesthesiol Scand. 47. 284-290 (2003)

Shinich Nakao：“丙泊酚对氯胺酮诱导的后扣带回和压后皮质 c-Fos 表达的抑制作用是由 GABAA 受体激活介导的”Acta Anaesthesiol Scand。

"Ketamine prevents hypocapnia-induced neuronal damage in the caudoputamen in chronic cerebral hypoperfusion rats"Anesthesiology. A758. (2002)

“氯胺酮可预防慢性脑灌注不足大鼠尾壳核中低碳酸血症引起的神经元损伤”麻醉学。

中尾 慎一: "薬物耽溺(Drug Abuse or Addiction)のメカニズム-麻酔関係薬物の耽溺を中心に"臨床麻酔(増刊号). 26. 413-425 (2002)

Shinichi Nakao：“药物滥用或成瘾的机制 - 关注麻醉相关药物的成瘾”《临床麻醉》（特刊）26. 413-425 (2002)。