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首页> 外文期刊>Addiction biology >Rapamycin attenuates the expression of cocaine-induced place preference and behavioral sensitization
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Rapamycin attenuates the expression of cocaine-induced place preference and behavioral sensitization

机译：雷帕霉素减弱可卡因诱导的位置偏爱和行为敏化的表达

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摘要

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that controls global protein synthesis, in part, by modulating translation initiation, a rate-limiting step for many mRNAs. Previous studies implicate mTOR in regulating stimulant-induced sensitization and antidepressive-like behavior in rodents, as well as drug craving in abstinent heroin addicts. To determine if signaling downstream of mTOR is affected by repeated cocaine administration in reward-associated brain regions, and if inhibition of mTOR alters cocaine-induced behavioral plasticity, C57BL/6J mice received four intraperitoneal (i.p.) injections of 15 mg/kg cocaine and levels of phosphorylated P70S6 kinase and ribosomal S6 protein-two translational regulators directly downstream of mTOR-were analyzed by immunoblotting across several brain regions. Cocaine place preference and locomotor sensitization were elicited by four pairings of cocaine with a distinct environment and the effects of mTOR inhibition were assessed by pre-treating the mice with 10 mg/kg rapamycin, 1 hour prior to: (1) each saline/cocaine conditioning session; (2) a post-conditioning test; or (3) a test for locomotor sensitization conducted at 3 weeks withdrawal. While systemic pre-treatment with 10 mg/kg rapamycin during conditioning failed to alter the development of a cocaine place preference or locomotor sensitization, pre-treatment prior to the post-conditioning test attenuated the expression of the place preference. Additionally, rapamycin pre-treatment prior to a cocaine challenge 3 weeks post-conditioning blocked the expression of the sensitized locomotor response. These findings suggest a role for mTOR activity, and perhaps translational control, in the expression of cocaine-induced place preference and locomotor sensitization.
机译：雷帕霉素（mTOR）的哺乳动物靶标是一种丝氨酸-苏氨酸激酶，可部分地通过调节翻译起始来控制整体蛋白质的合成，这是许多mRNA的限速步骤。先前的研究表明，mTOR可以调节啮齿动物中兴奋剂引起的致敏和抗抑郁样行为，以及戒除海洛因成瘾者对药物的渴望。为了确定在奖励相关的大脑区域反复给予可卡因是否会影响mTOR下游的信号传导，以及是否抑制mTOR改变了可卡因诱导的行为可塑性，C57BL / 6J小鼠接受了4次腹膜内（ip）注射，每次15 mg / kg可卡因，通过跨几个大脑区域的免疫印迹分析了mTOR下游的磷酸化P70S6激酶和核糖体S6蛋白-两个翻译调节子的水平。四对可卡因在不同的环境中引起可卡因位置偏爱和运动致敏作用，并且在下列情况下1小时前通过用10 mg / kg雷帕霉素对小鼠进行预处理来评估mTOR抑制作用：（1）每种盐水/可卡因适应期; （2）后处理测试;或（3）停药3周后进行运动敏化测试。尽管在调理过程中用10 mg / kg雷帕霉素进行全身预处理无法改变可卡因位置偏爱或运动敏化的发展，但在条件后测试之前进行的预处理会减弱位置偏爱的表达。另外，在可卡因激发之前，雷帕霉素预处理在调节后3周会阻断敏化运动反应的表达。这些发现表明在可卡因诱导的位置偏爱和运动敏化的表达中，mTOR活性以及翻译控制可能起作用。

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