Bach Patrick, de Timary Philippe, Gründer Gerhard, Cumming Paul
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany.
Department of Adult Psychiatry, Cliniques Universitaires Saint-Luc and Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.
Curr Top Behav Neurosci. 2023 Jan 14. doi: 10.1007/7854_2022_414.
Alcohol use disorder (AUD) is a serious public health problem in many countries, bringing a gamut of health risks and impairments to individuals and a great burden to society. Despite the prevalence of a disease model of AUD, the current pharmacopeia does not present reliable treatments for AUD; approved treatments are confined to a narrow spectrum of medications engaging inhibitory γ-aminobutyric acid (GABA) neurotransmission and possibly excitatory N-methyl-D-aspartate (NMDA) receptors, and opioid receptor antagonists. Molecular imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can open a window into the living brain and has provided diverse insights into the pathology of AUD. In this narrative review, we summarize the state of molecular imaging findings on the pharmacological action of ethanol and the neuropathological changes associated with AUD. Laboratory and preclinical imaging results highlight the interactions between ethanol and GABA A-type receptors (GABAR), but the interpretation of such results is complicated by subtype specificity. An abundance of studies with the glucose metabolism tracer fluorodeoxyglucose (FDG) concur in showing cerebral hypometabolism after ethanol challenge, but there is relatively little data on long-term changes in AUD. Alcohol toxicity evokes neuroinflammation, which can be tracked using PET with ligands for the microglial marker translocator protein (TSPO). Several PET studies show reversible increases in TSPO binding in AUD individuals, and preclinical results suggest that opioid-antagonists can rescue from these inflammatory responses. There are numerous PET/SPECT studies showing changes in dopaminergic markers, generally consistent with an impairment in dopamine synthesis and release among AUD patients, as seen in a number of other addictions; this may reflect the composite of an underlying deficiency in reward mechanisms that predisposes to AUD, in conjunction with acquired alterations in dopamine signaling. There is little evidence for altered serotonin markers in AUD, but studies with opioid receptor ligands suggest a specific up-regulation of the μ-opioid receptor subtype. Considerable heterogeneity in drinking patterns, gender differences, and the variable contributions of genetics and pre-existing vulnerability traits present great challenges for charting the landscape of molecular imaging in AUD.
酒精使用障碍（AUD）在许多国家都是一个严重的公共卫生问题，给个人带来一系列健康风险和损害，并给社会造成巨大负担。尽管存在AUD的疾病模型，但目前的药典并未提供可靠的AUD治疗方法；获批的治疗方法仅限于作用于抑制性γ-氨基丁酸（GABA）神经传递以及可能作用于兴奋性N-甲基-D-天冬氨酸（NMDA）受体的窄谱药物，以及阿片受体拮抗剂。正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）分子成像能够打开一扇通往活体大脑的窗口，并为AUD的病理学提供了多样的见解。在这篇叙述性综述中，我们总结了关于乙醇药理作用以及与AUD相关的神经病理学变化的分子成像研究结果。实验室和临床前成像结果突出了乙醇与GABA A型受体（GABAR）之间的相互作用，但此类结果的解释因亚型特异性而变得复杂。大量使用葡萄糖代谢示踪剂氟脱氧葡萄糖（FDG）的研究一致表明，乙醇激发后会出现大脑代谢减退，但关于AUD长期变化的数据相对较少。酒精毒性会引发神经炎症，可使用PET与用于小胶质细胞标记物转运体蛋白（TSPO）的配体来追踪。多项PET研究显示，AUD个体中TSPO结合可逆性增加，临床前结果表明阿片拮抗剂可减轻这些炎症反应。有大量PET/SPECT研究显示多巴胺能标记物发生变化，这通常与AUD患者中多巴胺合成和释放受损一致，正如在许多其他成瘾情况中所见；这可能反映了奖励机制潜在缺陷的综合作用，这种缺陷易导致AUD，同时伴有多巴胺信号传导的后天改变。几乎没有证据表明AUD中5-羟色胺标记物发生改变，但使用阿片受体配体的研究表明μ-阿片受体亚型存在特异性上调。饮酒模式的显著异质性、性别差异以及遗传因素和先前存在的易感性特征的不同贡献，给描绘AUD分子成像的全貌带来了巨大挑战。
