Neuroinflammation appears to contribute to neurotoxicity observed with heavy alcohol consumption. To assess whether chronic alcohol results in neuroinflammation we used PET and [¹¹C]PBR28, a ligand that binds to the 18-kDa translocator protein (TSPO), to compare participants with an alcohol use disorder (AUD: n = 19) with healthy controls (HC: n = 17), and alcohol-dependent (n = 9) with -nondependent rats (n = 10). Because TSPO is implicated in cholesterol's transport for steroidogenesis, we investigated whether plasma cholesterol levels influenced [¹¹C]PBR28 binding. [¹¹C]PBR28 binding did not differ between AUD and HC. However, when separating by TSPO genotype rs6971, we showed that medium-affinity binders AUD participants showed lower [¹¹C]PBR28 binding than HC in regions of interest (whole brain, gray and white matter, hippocampus, and thalamus), but no group differences were observed in high-affinity binders. Cholesterol levels inversely correlated with brain [¹¹C]PBR28 binding in combined groups, due to a correlation in AUD participants. In rodents, we observed no differences in brain [¹¹C]PBR28 uptake between alcohol-dependent and -nondependent rats. These findings, which are consistent with two previous [¹¹C]PBR28 PET studies, may indicate lower activation of microglia in AUD, whereas failure to observe alcohol effects in the rodent model indicate that species differences do not explain the discrepancy with prior rodent autoradiographic studies reporting increases in TSPO binding with chronic alcohol. However, reduced binding in AUD participants could also reflect competition from endogenous TSPO ligands such as cholesterol; and since the rs6971 polymorphism affects the cholesterol-binding domain of TSPO this could explain why differences were observed only in medium-affinity binders.

中文翻译：

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酒精中毒和胆固醇对脑中TSPO结合的影响：PET [11C] PBR28在人和啮齿动物中的研究。

大量饮酒可导致神经炎症。为了评估慢性酒精是否会导致神经炎症，我们使用了PET和[ ¹⁸ CDa易位蛋白（TSPO）结合的配体[ ¹¹ C] PBR28]，将参加者的酒精使用障碍（AUD：n = 19）与健康对照组（HC：n = 17）和酒精依赖性（n = 9），非依赖性大鼠（n = 10）。由于TSPO参与类固醇生成的胆固醇运输，因此我们研究了血浆胆固醇水平是否影响[ ¹¹ C] PBR28结合。[ ¹¹ C] PBR28结合在AUD和HC之间没有差异。然而，当通过TSPO基因型rs6971进行分离时，我们显示中等亲和力结合剂AUD参与者显示出更低的[ ¹¹C] PBR28在目标区域（整个大脑，灰白质，海马和丘脑）的结合比HC大，但在高亲和力结合剂中未观察到组差异。胆固醇水平与合并组中的脑[ ¹¹ C] PBR28结合呈负相关，这是因为AUD参与者之间存在相关性。在啮齿动物中，我们观察到酒精依赖性和非依赖性大鼠在大脑[ ¹¹ C] PBR28摄取方面没有差异。这些发现与之前的两个[ ¹¹C] PBR28 PET研究可能表明AUD中小胶质细胞的活化较低，而在啮齿动物模型中未观察到酒精作用表明，物种差异不能解释以前的啮齿动物放射自显影研究报告的TSPO与慢性酒精结合增加的差异。但是，AUD参与者的结合减少也可能反映了来自内源TSPO配体（例如胆固醇）的竞争。由于rs6971多态性影响TSPO的胆固醇结合结构域，因此可以解释为什么仅在中等亲和力结合剂中观察到差异。