中国药物警戒 ›› 2021, Vol. 18 ›› Issue (9): 821-825.
DOI: 10.19803/j.1672-8629.2021.09.06

• 基础与临床研究 • 上一篇    下一篇

大鼠自身给药模型评价右美托咪定的精神依赖作用

陈瑛1, 王立金2Δ, 李亮3, 贾艳丽1, 王雨1, 李子轲1, 韦娜1, 韩刚1, 吴纯启4, 董延生1,*   

  1. 1国科赛赋河北医药技术有限公司,河北 廊坊 065500;
    2解放军总医院京北医疗区麻醉科,北京 100094;
    3解放军总医院第六医学中心麻醉科,北京 100036;
    4国家北京药物安全评价研究中心,北京100850
  • 收稿日期:2020-11-04 出版日期:2021-09-15 发布日期:2021-09-18
  • 通讯作者: *董延生,男,博士,副研究员,新药安全评价研究。E-mail:dongyansheng@safeglp.com
  • 作者简介:陈瑛,女,硕士,实验师,新药非临床依赖性评价研究。Δ为并列第一作者。
  • 基金资助:
    重大新药创制国家科技重大专项2018年度（2018ZX09201017-003）

Evaluation of Psychological Dependency Potential of Dexmedetomidine in Rats in a Self-administration Study

CHEN Ying1, Wang Lijin2Δ, LI Liang3, JIA Yanli1, WANG Yu1, LI Zike1, WEI Na1, HAN Gang1, WU Chunqi4, DONG Yansheng1,*   

  1. 1Safe Medical Technology Co., Ltd., Langfang Hebei 065500, China;
    2Department of Anesthesiology, Beijing North Medical District of PLA General Hospital, Beijing 100094, China;
    3Department of Anesthesiology, the Sixth Medical Center of PLA General Hospital, Beijing 100036, China;
    4National Beijing Center for Drug Safety Evaluation and Research, Beijing 100850, China
  • Received:2020-11-04 Online:2021-09-15 Published:2021-09-18

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摘要： 目的 采用甲基苯丙胺（MA）建立的大鼠自身给药模型评价盐酸右美托咪定注射液（DEX）在疗效或疗效以上剂量的自身精神依赖作用。方法 ①自身训练实验：选用成功建立颈静脉通路的雄性SD大鼠30只,随机分为3组,即溶剂对照组（氯化钠注射液）,MA组（每次注射MA 50 μg/kg）,DEX组[每次注射DEX 7 μg/kg（d 1）、1 μg/kg（d 2）及0.5 μg/kg（d 3~7）],每天FR1程序下训练2 h,当MA组大鼠形成稳定的自身给药行为后3组动物训练结束。②替代实验：MA组大鼠在自身训练实验形成稳定的自身给药行为后用DEX（每次注射0.5 μg/kg）替代6 d后,再给予MA恢复训练10 d;记录大鼠有效鼻触次数与给药次数。结果 ①自身训练实验：与溶剂对照组相比,MA组大鼠在MA给药训练后2~7 d有效鼻触次数和给药次数均显著高于溶剂对照组（P≤ 0.05）,形成自身给药行为,提示实验体系建立成功。DEX组大鼠在给予DEX给药训练后除第2 天外,其他6 d有效鼻触次数和给药次数均无显著性差异（P > 0.05）。②替代实验：MA组大鼠在DEX替代给药训练后除最后1 d的给药次数外,其余5 d的有效鼻触次数和给药次数均显著低于MA训练稳定后3 d的均值（P≤ 0.05）。MA恢复给药训练后有效鼻触次数和给药次数除前2 d训练结果外,其余8 d均显著高于DEX替代给药训练后连续3 d的均值（P≤ 0.05）。结论 MA能够诱发大鼠形成稳定的自身给药行为,提示实验模型成功建立,实验体系可靠。DEX在本研究剂量下不能诱导大鼠形成自身给药行为,也不能替代MA成瘾大鼠觅药行为,提示在本实验条件下,DEX不具有精神依赖作用。

关键词: 右美托咪定, 甲基苯丙胺, 自身给药, 精神依赖

Abstract: Objective To evaluate the psychological dependence potential of DEX at an effective or higher dose by using self-administration in rats. Methods The dose design, grouping information and training procedures were as follows:①Self-training test: Thirty male SD rats that had their jugular vein access established were selected and randomly divided into three groups: the vehicle group, D-methamphetamine hydrochloride group (MA group) and DEX group. The rats in the vehicle group were injected intravenously with sodium chloride solution (0.25 mL/kg/infusion), those in the MA group with MA solution (dosage of 0.05 mg/kg/infusion), and those in the DEX group with DEX preparation (7 μg/kg/infusion (Day 1), 1 μg/kg/infusion (Day 2), 0.5 μg/kg/infusion (Day 3~7). The rats were trained for self-administration for 2 hours on each of the seven days under FR1.②Substitution test: During the self-training test, MA was substituted by DEX preparation (0.5 μg/kg/infusion) for 6 days before MA was given for 10 days as recovery training. The numbers of active pokes and times of infusion were recorded. Results ①Self-training test: According to the results of 7 days of training, the numbers of active pokes and times of infusion on Days 2 to 7 in the MA group were increased significantly compared with the control group (P≤ 0.05), suggesting that a proper test model was established that could be used to evaluate psychological dependence potential of DEX. The numbers of active pokes and times of infusion on Day 1 and Days 3 to 7 in the DEX group hardly changed (P > 0.05), which indicated that DEX did not induce psychological dependence potential. ②Substitution test: There was a significant decrease (P≤0.05) in the numbers of active pokes and times of infusion in the DEX group during the substitution except for Day 1, but there was a significant increase (P≤0.05) in the numbers of active pokes and times of infusion in the MA group during recovery except for the first 2 days, indicating that DEX could neither maintain the reinforcing effect of MA nor possess the psychological dependence potential of MA. Conclusion DEX itself does not have any positive reward effect or psychological dependence potential, so it cannot cause addiction or maintain the reinforcing effect of MA in this study.

Key words: dexmedetomidine, methamphetamine, self-administration, psychological dependence

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