健康与遗传心理学研究室知识库

药物戒断诱发的厌恶反应是促发强迫性觅药和复吸行为的重要因素。多巴胺系统参与阿片类药物的奖赏效应和戒断时的厌恶性效果。杏仁核是参与情绪性联想式学习的至关重要神经环路成分。杏仁核在成瘾药物有关的条件性因素诱发复吸及药物依赖的情绪性因素的作用得到关注。杏仁中央核是杏仁核多巴胺系统主要的作用亚区。
    为探讨阿片戒断诱发的条件性负性情绪的神经生物学机制，采用腹腔内注射纳络酮作为非条件刺激物，条件性位置实验箱的不同视觉和触觉线索为条件性刺激物。阿片依赖大鼠匹配以2次纳络酮诱发出戒断的条件性位置厌恶(CPA )反应。利用6-轻基多巴胺损毁技术及脑区微量给药技术考察杏仁中央核多巴胺系统对阿片戒断诱发厌恶性情绪的影响。
主要结果如下:
    不同剂量吗啡(起始剂量6, 12mg/kg)以20%递增给药10天致瘾。在偏倚的三箱式实验箱中，以纳络酮( 0.5, 1 mg/kg)与起始偏爱侧结合，使大鼠对实验箱两侧的选择性发生改变。结果表明:
    1.纳络酮诱发吗啡成瘾大鼠出现明显的CPA反应。
    2.不同剂量纳络酮对吗啡依赖大鼠CPA反应的获得没有明显差异。和大剂量纳络酮诱发的CPA反应相比，小剂量纳络酮诱发的CPA反应保持时间更长。
    3.大剂量纳络酮(1 mg/kg)可以诱发未使用吗啡大鼠产生厌恶性反应，但保持时间短。
4.纳络酮诱发依赖期大鼠出现CPA反应，而在戒断期大鼠却未出现。
    5. 6-轻基多巴胺损毁杏仁中央核多巴胺系统，阻断了阿片戒断诱发的条件性位置厌恶反应的获得。
    分别在纳络酮条件化训练前，杏仁中央核内给予多巴胺D1激动剂SKF38393 (1, 3Ng/}I), D1受体拮抗剂SCH23390(1, 3ug/uI), D2和D3受体的混合激动剂喳毗罗(1, 3Ng/闭)和D2拮抗剂雷氯必利(1, 4ug/ul)，考察多巴胺受体不同亚型对阿片戒断地负性情绪获得的影响。结果表明:
6. SKF38393激动杏仁中央核D1受体对阿片戒断诱发的条件性厌恶反应没有影响;而1、3ug/NI SCH23390阻滞D1受体，呈现剂量依赖性的抑制条件性位置厌恶反应的获得。
7.而当小剂量喳毗罗激活杏仁中央核D2受体时，也明显得抑制了位置厌恶反应的获得。而雷氯必利抑制D2受体则没有影响。
    综上所述，杏仁中央核多巴胺系统参与阿片戒断诱发的负性情绪的获得。阻滞D1受体、激活D2受体明显地干预了阿片戒断的负性情绪的获得。

    The negative affective state of opiate abstinence plays an important role in craving and relapse to compulsive drug use. Dopamine pathway is critically involved in both the rewarding properties of opiate drugs and the aversive effects of opiate withdrawal. The amygdala is a crucial component of the neuronal circuitry mediating emotional associative learning. Dopamine terminals in the amygdala are distributed primarily in the central nucleus of the amygdala (CeA).
   To  establish  the  model  of  conditioned  place  aversion  (CPA)  of morphine-treated rat, this study used different visual and tactual cues in the place conditioning apparatus as the conditioned stimulus (CS) and an injection of naloxone as the unconditioned stimulus (UCS). The CS was paired with UCS twice. The distinct CPA was induced in morphine dependence  rat.  6-OHDA  lesion  method  and  Intracerebral  drug microinjecting technique was used to assess the effect of dopamine system of CeA on the acquisition of CPA in morphine dependent rats.
    The main results are the following:
    Rats were made physically dependence with the initiative dose (6 mg/kg) of morphine by intraperitoneal injection in 20% increased every day within 10 days and were trained to develop CPA induced by naloxone (0.5 or 1.0 mg/kg) in a biased three-compartment conditioned place apparatus. The results showed that morphine-dependent rats with naloxone treatment produced distinct CPA. Though the effects of both high- and low-dose naloxone on the acquisition of CPA had no significant difference in dependent-rats, the conditional training with the low-dose naloxone induced more long-lasting CPA ,than that with high-dose. The place aversion was also induced by high-dose naloxone in naive rat, but lasted transiently. The conditional training with high- or low- dose naloxone produced CPA in the dependent rats, but not, in the abstinent rats.
    The acquisition of CPA in morphine dependence was impaired by bilateral microinjection 6-OHDA to CeA.
    To examine the role of CeA DA D1，D2 receptor in the acqusition of CPA in morphine dependence, the DA D1 agonist, SKF38393 (1，3Ng/NI), D1 antagonist, SCH23390 (1，3Ng/NI), D2/D3 agonist, quinpirole (1，3Ng/NI), D2 antagonist, raclopride (1，4Ng/NI) was infused into CeA prior naloxone conditioning. Pre-conditioning infusions of SCH23390 dose-dependently attenuated the acquisition of CPA. And  intra-CeA administration of low-dose quinpirole (1 Ng/NI) abolished the CPA,  but not high-dose (1 Ng/NI).
    In conclusion, dopamine system of CeA was involved in the negative affective components of morphine abstinence. And dopamine D1 receptor and D2 receptor within the CeA contributes to the acquisition of aversive emotion of opiate withdrawal.