Rapamycin prevents drug seeking via disrupting reconsolidation of reward memory in rats
Rapamycin prevents drug seeking via disrupting reconsolidation of reward memory in rats
复制标题
雷帕霉素通过破坏大鼠奖赏记忆的重新巩固来防止药物寻求。
DOI：
10.1017/s1461145713001156
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发表时间：
2014-01-01
影响因子：
4.8
通讯作者：
Li, Yanqin
中科院分区：
文献类型：
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作者：
Lin, Jue;Liu, Lingqi;Li, Yanqin
在药物奖励效应和环境线索之间发展的适应不良的药物记忆导致难以预防药物复吸。已建立的奖励记忆可以在其重新激活后通过药物干预来破坏。雷帕霉素是哺乳动物雷帕霉素靶蛋白（mTOR）激酶的抑制剂，参与多种记忆巩固过程。然而，在药物记忆再巩固方面，它的特征还不太清楚。使用条件性位置偏爱（CPP）程序，我们研究了全身给予雷帕霉素对大鼠药物记忆再巩固的影响。我们发现全身给予雷帕霉素（0.1或10 mg/kg，i. p.）再次暴露于药物配对环境后，1d后CPP表达呈剂量依赖性降低，这种作用可持续至14 d，且不能被吗啡预注所逆转。雷帕霉素对吗啡相关记忆的影响是特定于药物配对的背景，当大鼠暴露于盐水配对的背景或家庭环境时，雷帕霉素对随后的CPP表达没有影响。这些结果表明，在记忆再激活后全身给予雷帕霉素可以通过破坏大鼠吗啡记忆再巩固来持续抑制大鼠的觅药行为。此外，雷帕霉素对记忆再巩固的影响在可卡因CPP和酒精CPP中重现。此外，雷帕霉素没有诱导条件性位置厌恶，对自发活动和焦虑行为没有影响。这些发现表明，雷帕霉素可以清除大鼠获得的药物CPP，并且mTOR活性在药物再巩固中起重要作用，并且是药物复发所必需的。
The maladaptive drug memory developed between the drug-rewarding effect and environmental cues contributes to difficulty in preventing drug relapse. Established reward memories can be disrupted by pharmacologic interventions following their reactivation. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) kinase, has been proved to be involved in various memory consolidation. However, it is less well characterized in drug memory reconsolidation. Using a conditioned place preference (CPP) procedure, we examined the effects of systemically administered rapamycin on reconsolidation of drug memory in rats. We found that systemically administered rapamycin (0.1 or 10mg/kg, i.p.) after re-exposure to drug-paired environment, dose dependently decreased the expression of CPP 1d later, and the effect lasted for up to 14d and could not be reversed by a priming injection of morphine. The effect of rapamycin on morphine-associated memory was specific to drug-paired context, and rapamycin had no effect on subsequent CPP expression when rats were exposed to saline-paired context or homecage. These results indicated that systemic administration of rapamycin after memory reactivation can persistently inhibit the drug seeking behaviour via disruption of morphine memory reconsolidation in rats. Additionally, the effect of rapamycin on memory reconsolidation was reproduced in cocaine CPP and alcohol CPP. Furthermore, rapamycin did not induce conditioned place aversion and had no effect on locomotor activity and anxiety behaviour. These findings suggest that rapamycin could erase the acquired drug CPP in rats, and that mTOR activity plays an important role in drug reconsolidation and is required for drug relapse.