本文選題：多巴胺 + 多巴胺D3受體�。� 參考：《中南大學》2013年碩士論文

【摘要】：目的阿片成癮(吸毒)是關(guān)乎到國家安全、社會穩(wěn)定、人口素質(zhì)和公共衛(wèi)生水平的重大問題。本課題旨在探討多巴胺D3受體是否參與阿片成癮的調(diào)控,特異性地作用于該受體后是否影響阿片成癮的形成及復吸。 方法采用自身給藥(self-administration, SA)、條件性位置偏愛(conditioned place preference, CPP)和行為敏化(behavioral sensitization, BS)動物模型觀察Y-QA14自身依賴性及抗阿片成癮的藥效學作用。 結(jié)果1.Y-QA14自身致成癮潛能及可能副作用 在CPP模型中,Y-QA14(6.25,12.5,25mg/kg, i.p.)不能誘發(fā)小鼠形成條件性位置偏愛或偏惡,表明其自身無成癮性。 在自發(fā)活動實驗中,單次給予Y-QA14(3.125,6.25,12.5,25,50mg/kg; i.p.),僅在50mg/kg劑量抑制小鼠自發(fā)活動。推測此高劑量下的作用可能與其影響其他受體功能相關(guān)。連續(xù)10天多次給予Y-QA14(25和50mg/kg, i.p.),對小鼠自發(fā)活動無影響。 2.Y-QA14和Y-QA31具有抗阿片正性強化作用 在SA模型中,Y-QA14(25mg/kg,50mg/kg; i.p.)和Y-QA31(25mg/kg; i.p.)可顯著抑制大鼠海洛因(0.025mg/kg, i.v.) SA行為。在大鼠CPP模型中,Y-QA14(6.25,12.5,25mg/kg, i.p.)劑量依賴地顯著抑制嗎啡(lOmg/kg, s.c.)誘發(fā)大鼠CPP的表達。在小鼠BS模型中,Y-QA14(6.25,12.5,25mg/kg,i.p.)顯著抑制嗎啡(10mg/kg,s.c.)誘發(fā)小鼠BS的形成。以上結(jié)果提示Y-QA14選擇性地阻斷D3R后,能干預阿片正性強化作用,提示D3R參與了阿片獎賞作用的發(fā)揮。 3.防阿片復吸的作用 在大鼠SA模型中,Y-QA14(25mg/kg, i.p.)可以顯著抑制海洛因(0.25mg/kg, i.p.)誘發(fā)的大鼠SA復吸行為；在大鼠CPP模型中,在大鼠條件性戒斷時給予Y-QA14(6.25,12.5,25mg/kg, i.p.)可以劑量依賴地降低嗎啡(5mg/kg, s.c.)誘發(fā)CPP的復吸；在小鼠CPP模型中,自然戒斷過程伴隨給予Y-QA14(6.25,12.5,25mg/kg, i.p.)可以加速CPP熄滅,并對隨后嗎啡(5mg/kg, s.c.)誘發(fā)小鼠CPP的復吸有抑制趨勢,但無顯著性差異。在小鼠BS模型中,嗎啡(10mg/kg, s.c.)誘發(fā)小鼠BS形成過程中伴隨給予Y-QA14(6.25,12.5,25mg/kg, i.p.)或在激發(fā)期單次給予Y-QA14(25mg/kg, i.p.)均可顯著抑制隨后嗎啡(5mg/kg,s.c.)誘發(fā)小鼠BS的復吸。這些結(jié)果提示選擇性的阻斷D3R后,可有效預防小劑量藥物引起的阿片復吸。 結(jié)論綜上所述,Y-QA14本身不具有致依賴潛能,但通過特異性拮抗D3R抑制阿片成癮的發(fā)生、發(fā)展及復吸。通過本課題的研究,為闡明D3R在阿片成癮中的作用以及研發(fā)D3R阻斷劑治療阿片成癮及復吸提供了實驗依據(jù)。
[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.
【學位授予單位】：中南大學
【學位級別】：碩士
【學位授予年份】：2013
【分類號】：R749.64

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