Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice
Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice
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DOI：
10.1038/npp.2013.256
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发表时间：
2014-02-01
影响因子：
7.6
通讯作者：
Becker, Howard C.
中科院分区：
文献类型：
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作者：
Griffin, William C., III;Haun, Harold L.;Becker, Howard C.
使用一个完善的酒精依赖和复发的模型，本研究探讨了适应性的approachamatergic传输的核神经元（NAc）和他们的作用，调节自愿饮酒。首先训练小鼠以自由选择、有限进入（2小时/天）的模式饮用乙醇。一组（EtOH小鼠）接受重复的每周周期的慢性间歇性乙醇（CIE）暴露，中间有几周的测试饮酒期，而其余的小鼠（CTL小鼠）进行类似的治疗，但没有接受CIE治疗。在CIE暴露的重复循环中，EtOH小鼠表现出饮酒的显著增加（高达B3.5 g/kg），而CTL小鼠的饮酒在基线水平（2-2.5 g/kg）保持相对稳定。使用体内微透析程序，与CTL小鼠相比，EtOH小鼠NAc中的细胞外谷氨酸（GLU（EX））水平增加约两倍，并且在最终CIE暴露后7天观察到这种差异，表明这种高谷氨酸能状态持续超过急性戒断。这一发现促使更多的研究检查在CIE模型中NAc中的葡萄糖操纵GLU（EX）对乙醇饮用的影响。将非选择性谷氨酸再摄取拮抗剂苏式-β-苄氧基天冬氨酸（TBOA）双侧微量注射到NAc中，发现非依赖性（CTL）小鼠的饮酒量呈剂量依赖性增加至依赖性（EtOH）小鼠达到的水平。TBOA还进一步增加了EtOH小鼠的饮酒量。相比之下，通过双侧注射代谢型谷氨酸受体-2/3激动剂LY 379268减少NAc中的谷氨酸能传递将依赖性（EtOH）小鼠的饮酒减少到非依赖性（CTL）水平，而在减少CTL小鼠的乙醇消耗方面具有更适度的效果。两者合计，这些数据支持在NAc中调节乙醇饮用的重要作用。此外，这些结果表明，乙醇依赖性产生的适应，有利于提高谷氨酸活性的NAc，这反过来又促进过度的乙醇消耗与依赖。
Using a well-established model of ethanol dependence and relapse, this study examined adaptations in glutamatergic transmission in the nucleus accumbens (NAc) and their role in regulating voluntary ethanol drinking. Mice were first trained to drink ethanol in a free-choice, limited access (2 h/day) paradigm. One group (EtOH mice) received repeated weekly cycles of chronic intermittent ethanol (CIE) exposure with intervening weeks of test drinking sessions, whereas the remaining mice (CTL mice) were similarly treated but did not receive CIE treatment. Over repeated cycles of CIE exposure, EtOH mice exhibited significant escalation in drinking (up to B3.5 g/kg), whereas drinking remained relatively stable at baseline levels (2-2.5 g/kg) in CTL mice. Using in vivo microdialysis procedures, extracellular glutamate (GLU(EX)) levels in the NAc were increased approximately twofold in EtOH mice compared with CTL mice, and this difference was observed 7 days after final CIE exposure, indicating that this hyperglutamatergic state persisted beyond acute withdrawal. This finding prompted additional studies examining the effects of pharmacologically manipulating GLU(EX) in the NAc on ethanol drinking in the CIE model. The non-selective glutamate reuptake antagonist, threo-beta-benzyloxyaspartate (TBOA), was bilaterally microinjected into the NAc and found to dose-dependently increase drinking in nondependent (CTL) mice to levels attained by dependent (EtOH) mice. TBOA also further increased drinking in EtOH mice. In contrast, reducing glutamatergic transmission in the NAc via bilateral injections of the metabotropic glutamate receptor-2/3 agonist LY379268 reduced drinking in dependent (EtOH) mice to nondependent (CTL) levels, whereas having a more modest effect in decreasing ethanol consumption in CTL mice. Taken together, these data support an important role of glutamatergic transmission in the NAc in regulating ethanol drinking. Additionally, these results indicate that ethanol dependence produces adaptations that favor elevated glutamate activity in the NAc which, in turn, promote excessive levels of ethanol consumption associated with dependence.