Inactivation of the lateral orbitofrontal cortex increases drinking in ethanol-dependent but not non-dependent mice.
Inactivation of the lateral orbitofrontal cortex increases drinking in ethanol-dependent but not non-dependent mice.
复制标题
侧眶额皮质的失活会增加乙醇依赖性但非依赖性小鼠的饮用。
DOI：
10.1016/j.neuropharm.2016.03.031
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发表时间：
2016-08
影响因子：
4.7
通讯作者：
Woodward JJ
中科院分区：
文献类型：
--
作者：
den Hartog C;Zamudio-Bulcock P;Nimitvilai S;Gilstrap M;Eaton B;Fedarovich H;Motts A;Woodward JJ
长期摄入乙醇会影响对学习、记忆、认知和决策至关重要的皮质区域。皮质功能的缺陷可能会通过阻碍个体控制饮酒的能力而导致酗酒障碍。本实验室先前的研究表明，急性乙醇会降低外侧眶额皮质（LOFC）神经元的活性，而慢性暴露会损害依赖于LOFC的反转学习，并诱导LOFC兴奋性发生变化。尽管有这些发现，LOFC神经元在乙醇摄入中的作用尚不清楚。为了解决这个问题，我们研究了成年C57Bl/6J小鼠的乙醇摄入情况，这些小鼠的LOFC接受了兴奋性毒性损伤或抑制性DREADD（由设计药物特异性激活的设计受体）的病毒注射。在7周内每隔一天给予浓度逐渐升高的乙醇（3 - 40%）期间，假手术组和损伤组小鼠之间在乙醇摄入量上没有观察到差异。在乙醇溶液中分别掺入糖精（0.2%）或奎宁（0.06 mM）时，两组小鼠对40%乙醇溶液的摄入量分别出现类似的增加或减少。使用一种产生依赖的慢性间歇性乙醇（CIE）蒸汽暴露模型，我们发现蒸汽处理前假手术组和损伤组小鼠的基础饮酒量没有差异。与空气处理的动物相比，CIE使两组小鼠的饮酒量都增加了，并且与CIE假手术对照组相比，CIE处理的损伤组小鼠的乙醇摄入量进一步增加。当在乙醇溶液中加入奎宁的第一周，这种效应持续存在，但在接下来的2周内，CIE损伤组小鼠的摄入量下降到对照水平。在病毒注射的小鼠中，抑制性DREADD受体的表达没有改变基础饮酒量，并且重复的CIE暴露周期使DREADD组和病毒对照组的饮酒量都增加了。与损伤研究一致，氯氮平 - N - 氧化物（CNO）处理仅在CIE暴露的DREADD小鼠中进一步增加了摄入量，而在空气处理的小鼠中没有变化。这些结果表明，LOFC对于非依赖小鼠乙醇摄入的起始和维持并不关键，但可能调节在依赖过程中观察到的饮酒量增加。
Long-term consumption of ethanol affects cortical areas that are important for learning and memory, cognition, and decision-making. Deficits in cortical function may contribute to alcohol-abuse disorders by impeding an individual’s ability to control drinking. Previous studies from this laboratory show that acute ethanol reduces activity of lateral orbitofrontal cortex (LOFC) neurons while chronic exposure impairs LOFC-dependent reversal learning and induces changes in LOFC excitability. Despite these findings, the role of LOFC neurons in ethanol consumption is unknown. To address this issue, we examined ethanol drinking in adult C57Bl/6J mice that received an excitotoxic lesion or viral injection of the inhibitory DREADD (designer receptor exclusively activated by designer drug) into the LOFC. No differences in ethanol consumption were observed between sham and lesioned mice during access to increasing concentrations of ethanol (3–40%) every other day for 7 weeks. Adulterating the ethanol solution with saccharin (0.2%) or quinine (0.06 mM) enhanced or inhibited, respectively, consumption of the 40% ethanol solution similarly in both groups. Using a chronic intermittent ethanol (CIE) vapor exposure model that produces dependence, we found no difference in baseline drinking between sham and lesioned mice prior to vapor treatments. CIE enhanced drinking in both groups as compared to air-treated animals and CIE treated lesioned mice showed an additional increase in ethanol drinking as compared to CIE sham controls. This effect persisted during the first week when quinine was added to the ethanol solution but consumption decreased to control levels in CIE lesioned mice in the following 2 weeks. In viral injected mice, baseline drinking was not altered by expression of the inhibitory DREADD receptor and repeated cycles of CIE exposure enhanced drinking in DREADD and virus control groups. Consistent with the lesion study, treatment with clozapine-N-oxide (CNO) further enhanced consumption only in CIE exposed DREADD mice with no change in air-treated mice. These results suggest that the LOFC is not critical for the initiation and maintenance of ethanol drinking in non-dependent mice, but may regulate the escalated drinking observed during dependence.