Brain matrix metalloproteinases (MMPs) have been recently implicated in alcohol addiction; however, the molecular mechanisms remain poorly understood. Matrix metalloproteinase-9 (MMP-9), an extrasynaptic protease, is the best described MMP that is thought to regulate addictive behavior. In the present study, the effect of MMP-9 overexpression on hippocampal neuron plasticity and alcoholic behavior was assessed in spontaneous alcohol drinking mice. Two-bottle choice model showed that the overexpression of MMP-9 in the hippocampus developed by adeno-associated virus (AAV) could decrease alcohol consumption and preference, but did not affect taste preference, which was tested using saccharin or quinine solutions. Dendritic spines number of hippocampal neurons was observed by Golgi staining. Compared with the alcohol treatment group, the density of dendritic spines in the hippocampus of alcohol drinking mice was decreased in alcohol + MMP-9 group. Western blot analysis indicated that GluN1 expression in the hippocampus of alcohol drinking group was lower than that in the control group, while the expression of GluN1 was increased in MMP-9 overexpressing mice. MMP-9 also regulated the depolymerization of actin filaments, which induced behavioral changes in mice. Taken together, overexpression of MMP-9 in the hippocampal neurons of mice resulted in decreased dendritic spine density and F-actin/G-actin ratio, which might be the crucial reason for the significant decrease in alcohol consumption in alcohol drinking mice. MMP-9 might be considered as a novel target studying the molecular mechanism of alcohol drinking.

中文翻译：

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基质金属蛋白酶9的过表达调节小鼠海马突触的可塑性，并降低其饮酒量和偏好。

脑基质金属蛋白酶（MMPs）最近与酒精成瘾有关。但是，分子机制仍然知之甚少。基质金属蛋白酶9（MMP-9）是一种突触外蛋白酶，是描述得最好的MMP，被认为可以调节成瘾行为。在本研究中，在自发饮酒的小鼠中评估了MMP-9过表达对海马神经元可塑性和酒精行为的影响。两瓶选择模型显示，腺相关病毒（AAV）在海马中过度表达MMP-9可以减少酒精消耗和偏好，但不影响口味偏好，这是通过糖精或奎宁溶液进行测试的。通过高尔基染色观察到海马神经元的树突棘数量。与酒精治疗组相比，酒精+ MMP-9组饮酒小鼠海马树突棘密度降低。Western印迹分析表明，饮酒组海马中GluN1的表达低于对照组，而在过量表达MMP-9的小鼠中GluN1的表达升高。MMP-9还调节肌动蛋白丝的解聚，从而诱导小鼠的行为改变。两者合计，小鼠海马神经元中MMP-9的过度表达导致树突棘密度和F-肌动蛋白/ G-肌动蛋白比降低，这可能是饮酒小鼠饮酒量显着减少的关键原因。MMP-9可能被认为是研究饮酒分子机制的新靶标。