Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado.
Institute of Cognitive Science, University of Colorado Boulder, Boulder, Colorado.
Addict Biol. 2020 Jan;25(1):e12684. doi: 10.1111/adb.12684. Epub 2018 Oct 29.
Chronic exposure to alcohol and other drugs of abuse has been associated with deleterious consequences, including functional connectivity deficits within neural networks associated with executive control. Altered functional connectivity within the executive control network (ECN) might underlie the progressive inability to control consumption of alcohol and other drugs as substance use disorders progress. Genetic and epigenetic factors have been associated with substance use disorders (SUDs). For example, dopamine receptor 2 (DRD2) functioning has been associated with alcohol use disorder (AUD) and related phenotypes, including correlates of executive functioning. The present study aims to explore the relationship between a continuous measure of alcohol-related problems, epigenetic markers (methylation) within the DRD2 gene, and functional connectivity within the ECN among a sample of polysubstance users. A community sample of 658 subjects, whose consumption of alcohol, nicotine, and cannabis span across a spectrum of quantity and frequency of use, were obtained across previous studies in polysubstance using populations. Resting state functional magnetic resonance imaging was analyzed to identify intrinsic connectivity networks using a priori regions of interest. Methylation measurement of functionally relevant sites within the DRD2 gene was achieved via pyrosequencing. Regression-based models, including mediation and moderation models, tested the association between DRD2 methylation, functional connectivity within intrinsic neural networks (including the ECN), and severity of alcohol problems. Results suggest that average DRD2 methylation was negatively associated with right ECN (RECN) and left ECN (LECN) connectivity, but not associated with other networks tested, and DRD2 methylation was significantly associated with alcohol problems severity. Mediation models were not supported, although moderation models suggested that connectivity between edges within the RECN moderated the relationship between DRD2 methylation and AUD severity. Results support a theoretical model in which epigenetic factors are associated with neurobiological correlates of alcohol consumption among a sample of polysubstance users.
慢性暴露于酒精和其他滥用药物与有害后果有关，包括与执行控制相关的神经网络中的功能连接缺陷。执行控制网络（ECN）内功能连接的改变可能是物质使用障碍进展导致逐渐无法控制酒精和其他药物消费的基础。遗传和表观遗传因素与物质使用障碍（SUD）有关。例如，多巴胺受体 2（DRD2）功能与酒精使用障碍（AUD）和相关表型有关，包括执行功能的相关指标。本研究旨在探索酒精相关问题的连续度量、DRD2 基因内表观遗传标记（甲基化）以及多药物使用者样本中 ECN 内功能连接之间的关系。通过先前在多药物使用人群中进行的研究获得了一个包含 658 名受试者的社区样本，这些受试者的酒精、尼古丁和大麻消费在数量和使用频率上都有一定程度的跨越。使用静息状态功能磁共振成像分析来确定使用先验感兴趣区域的内在连通性网络。通过焦磷酸测序实现 DRD2 基因内功能相关位点的甲基化测量。基于回归的模型，包括中介和调节模型，测试了 DRD2 甲基化、内在神经网络（包括 ECN）内的功能连接与酒精问题严重程度之间的关联。结果表明，平均 DRD2 甲基化与右 ECN（RECN）和左 ECN（LECN）的连接呈负相关，但与其他测试网络无关，DRD2 甲基化与酒精问题的严重程度显著相关。中介模型未得到支持，尽管调节模型表明 RECN 内边缘之间的连接调节了 DRD2 甲基化与 AUD 严重程度之间的关系。结果支持了这样一种理论模型，即表观遗传因素与多药物使用者样本中酒精消费的神经生物学相关因素有关。
