多巴胺D3受体阻断剂抗阿片成瘾研究

发布时间：2018-05-07 04:35

本文选题：多巴胺 + 多巴胺D3受体　；参考：《中南大学》2013年硕士论文

【摘要】：目的阿片成瘾(吸毒)是关乎到国家安全、社会稳定、人口素质和公共卫生水平的重大问题。本课题旨在探讨多巴胺D3受体是否参与阿片成瘾的调控,特异性地作用于该受体后是否影响阿片成瘾的形成及复吸。方法采用自身给药(self-administration, SA)、条件性位置偏爱(conditioned place preference, CPP)和行为敏化(behavioral sensitization, BS)动物模型观察Y-QA14自身依赖性及抗阿片成瘾的药效学作用。结果1.Y-QA14自身致成瘾潜能及可能副作用在CPP模型中,Y-QA14(6.25,12.5,25mg/kg, i.p.)不能诱发小鼠形成条件性位置偏爱或偏恶,表明其自身无成瘾性。在自发活动实验中,单次给予Y-QA14(3.125,6.25,12.5,25,50mg/kg; i.p.),仅在50mg/kg剂量抑制小鼠自发活动。推测此高剂量下的作用可能与其影响其他受体功能相关。连续10天多次给予Y-QA14(25和50mg/kg, i.p.),对小鼠自发活动无影响。 2.Y-QA14和Y-QA31具有抗阿片正性强化作用在SA模型中,Y-QA14(25mg/kg,50mg/kg; i.p.)和Y-QA31(25mg/kg; i.p.)可显著抑制大鼠海洛因(0.025mg/kg, i.v.) SA行为。在大鼠CPP模型中,Y-QA14(6.25,12.5,25mg/kg, i.p.)剂量依赖地显著抑制吗啡(lOmg/kg, s.c.)诱发大鼠CPP的表达。在小鼠BS模型中,Y-QA14(6.25,12.5,25mg/kg,i.p.)显著抑制吗啡(10mg/kg,s.c.)诱发小鼠BS的形成。以上结果提示Y-QA14选择性地阻断D3R后,能干预阿片正性强化作用,提示D3R参与了阿片奖赏作用的发挥。 3.防阿片复吸的作用在大鼠SA模型中,Y-QA14(25mg/kg, i.p.)可以显著抑制海洛因(0.25mg/kg, i.p.)诱发的大鼠SA复吸行为；在大鼠CPP模型中,在大鼠条件性戒断时给予Y-QA14(6.25,12.5,25mg/kg, i.p.)可以剂量依赖地降低吗啡(5mg/kg, s.c.)诱发CPP的复吸；在小鼠CPP模型中,自然戒断过程伴随给予Y-QA14(6.25,12.5,25mg/kg, i.p.)可以加速CPP熄灭,并对随后吗啡(5mg/kg, s.c.)诱发小鼠CPP的复吸有抑制趋势,但无显著性差异。在小鼠BS模型中,吗啡(10mg/kg, s.c.)诱发小鼠BS形成过程中伴随给予Y-QA14(6.25,12.5,25mg/kg, i.p.)或在激发期单次给予Y-QA14(25mg/kg, i.p.)均可显著抑制随后吗啡(5mg/kg,s.c.)诱发小鼠BS的复吸。这些结果提示选择性的阻断D3R后,可有效预防小剂量药物引起的阿片复吸。结论综上所述,Y-QA14本身不具有致依赖潜能,但通过特异性拮抗D3R抑制阿片成瘾的发生、发展及复吸。通过本课题的研究,为阐明D3R在阿片成瘾中的作用以及研发D3R阻断剂治疗阿片成瘾及复吸提供了实验依据。
[Abstract]:Objective opioid addiction is a major problem related to national security, social stability, population quality and public health. The purpose of this study was to investigate whether dopamine D 3 receptor is involved in the regulation of opioid addiction, and whether the dopamine D 3 receptor specifically affects the formation and relapse of opioid addiction. Methods the animal models of self-administration, conditioned place preference, CPP) and behavioral sensitization were used to observe the self-dependence of Y-QA14 and the pharmacodynamics of anti-opioid addiction. Results the potential of 1.Y-QA14 to induce addiction and its possible side effects In the CPP model, Y-QA14 6.25 (12.5mg / kg, i.p..) Mice could not be induced to form conditioned place preference or vice, indicating that they were not addictive. In the spontaneous activity experiment, Y-QA14 was given to 3.125A6.256.25A12.5U 25mg / kg for a single time, and i.p., only at the dose of 50mg/kg, the spontaneous activity was inhibited in mice. It is speculated that the action at this high dose may be related to its effect on other receptor functions. Y-QA14(25 and 50 mg / kg, i.p.., for more than 10 days, had no effect on the spontaneous activity of mice. 2.Y-QA14 and Y-QA31 have positive anti-opioid enhancement effect In SA model, Y-QA14, 25 mg / kg, 50 mg / kg; i.p..) And Y-QA31C 25mg / kg; i.p.) Can significantly inhibit heroin in rats by 0.025 mg / kg, i.v.) SA behavior. In the rat CPP model, Y- QA14, 6.25, 12.5, 25 mg / kg, i.p.) Significant dose-dependent inhibition of morphine omg / kg, s.c. The expression of CPP was induced in rats. In a mouse BS model, Y- QA14, 6.25, 12.5, 25 mg / kg, i.p.. Significantly inhibited morphine 10 mg / kg. To induce the formation of BS in mice. These results suggest that Y-QA14 can interfere with opioid positive enhancement after selective blocking of D3R, suggesting that D3R is involved in the role of opioid reward. 3. Effect of anti-opioid relapse 25 mg / kg, i.p.., in rat SA model Significant inhibition of 0.25 mg / kg, i.p..) Induced SA relapse in rats; in rat CPP model, Y-QA146.25C12.5 mg / kg, i.p.during conditioned abstinence in rats Can reduce morphine by 5 mg / kg, s.c.in a dose-dependent manner. In mouse CPP model, the spontaneous withdrawal was accompanied by Y-QA14 6.25 ~ 12.5 mg / kg, i.p.) It speeds up the CPP extinguishment, and then 5 mg / kg, s.c.of morphine. The relapse induced by CPP in mice showed a tendency of inhibition, but there was no significant difference. In the mouse BS model, morphine 10 mg / kg, s.c. The induction of BS in mice was accompanied by the administration of Y-QA14 6.25 ~ 12.5g / kg, i.p.. Or single dose of Y-QA14 25 mg / kg, i.p.during the excitation period) All of them were significantly inhibited by morphine (5 mg / kg). To induce the relapse of BS in mice. These results suggest that selective blocking of D 3 R can effectively prevent low dose opioid relapse. Conclusion in conclusion, Y-QA14 has no dependence potential, but inhibits the occurrence, development and relapse of opioid addiction through specific antagonism of D3R. Through the research of this subject, it provides experimental basis for clarifying the role of D3R in opioid addiction and developing D3R blocker for the treatment of opioid addiction and relapse.
【学位授予单位】：中南大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R749.64

【参考文献】