Laboratory of Neurobiology, the Nencki Institute, Warsaw.
Laboratory of Neuroinformatics, the Nencki Institute, Warsaw.
Biol Psychiatry. 2017 Jun 1;81(11):907-917. doi: 10.1016/j.biopsych.2016.12.026. Epub 2017 Jan 5.
Dysfunction of the glutamatergic system has been implicated in alcohol addiction; however, the molecular underpinnings of this phenomenon are still poorly understood. In the current study we have investigated the possible function of matrix metalloproteinase-9 (MMP-9) in alcohol addiction because this protein has recently emerged as an important regulator of excitatory synaptic plasticity.
For long-term studies of alcohol drinking in mice we used IntelliCages. Dendritic spines were analyzed using Diolistic staining with DiI. Whole-cell patch clamp was used to assess silent synapses. Motivation for alcohol in human subjects was assessed on the basis of a Semi-Structured Assessment for the Genetics of Alcoholism interview.
Mice devoid of MMP-9 (MMP-9 knockout) drank as much alcohol as wild-type animals; however, they were impaired in alcohol seeking during the motivation test and withdrawal. The deficit could be rescued by overexpression of exogenous MMP-9 in the central nucleus of the amygdala (CeA). Furthermore, the impaired alcohol seeking was associated with structural alterations of dendritic spines in the CeA and, moreover, whole-cell patch clamp analysis of the basal amygdala to CeA projections showed that alcohol consumption and withdrawal were associated with generation of silent synapses. These plastic changes were impaired in MMP-9 knockout mice. Finally, C/T polymorphism of MMP-9 gene at position -1562, which upregulates MMP-9 expression, correlated with increased motivation for alcohol in alcoholics.
In aggregate, our results indicate a novel mechanism of alcohol craving that involves MMP-9-dependent synaptic plasticity in CeA.
谷氨酸能系统功能障碍与酒精成瘾有关；然而，这一现象的分子基础仍知之甚少。在目前的研究中，我们研究了基质金属蛋白酶-9（MMP-9）在酒精成瘾中的可能作用，因为这种蛋白质最近已成为兴奋性突触可塑性的重要调节因子。
我们使用 IntelliCages 对小鼠进行长期饮酒研究。使用 DiI 进行 Diolistic 染色分析树突棘。使用全细胞膜片钳评估沉默突触。根据半结构化酒精成瘾遗传学评估访谈评估人类受试者对酒精的动机。
缺乏 MMP-9 的小鼠（MMP-9 敲除）与野生型动物一样饮用大量酒精；然而，它们在动机测试和戒断期间的酒精寻求行为受损。在杏仁中央核（CeA）中过表达外源性 MMP-9 可以挽救这种缺陷。此外，受损的酒精寻求与 CeA 中的树突棘结构改变有关，而且，基底杏仁核到 CeA 投射的全细胞膜片钳分析表明，酒精消耗和戒断与沉默突触的产生有关。这些塑性变化在 MMP-9 敲除小鼠中受损。最后，MMP-9 基因 -1562 位置的 C/T 多态性（可上调 MMP-9 表达）与酗酒者对酒精的动机增加有关。
总的来说，我们的研究结果表明了一种新的酒精渴求机制，涉及 CeA 中 MMP-9 依赖性突触可塑性。
