Land Michelle A, Ramesh Divya, Miller Aaron L, Pyles Richard B, Cunningham Kathryn A, Moeller F Gerard, Anastasio Noelle C
Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States.
Department of Psychiatry and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, United States.
Front Psychiatry. 2020 Jun 10;11:532. doi: 10.3389/fpsyt.2020.00532. eCollection 2020.
Relapse during abstinence in cocaine use disorder (CUD) is often hastened by high impulsivity (predisposition toward rapid unplanned reactions to stimuli without regard to negative consequences) and high cue reactivity (e.g., attentional bias towards drug reward stimuli). A deeper understanding of the degree to which individual biological differences predict or promote problematic behaviors may afford opportunities for clinical refinement and optimization of CUD diagnostics and/or therapies. Preclinical evidence implicates serotonin (5-HT) neurotransmission through the 5-HT receptor (5-HTR) as a driver of individual differences in these relapse-related behaviors. Regulation of 5-HTR function occurs through many mechanisms, including DNA methylation of the gene, an epigenetic modification linked with the memory of gene-environment interactions. In the present study, we tested the hypothesis that methylation of the may associate with relapse-related behavioral vulnerability in cocaine-dependent participants versus healthy controls. Impulsivity was assessed by self-report (Barratt Impulsiveness Scale; BIS-11) and the delay discounting task, while levels of cue reactivity were determined by performance in the cocaine-word Stroop task. Genomic DNA was extracted from lymphocytes and the bisulfite-treated DNA was subjected to pyrosequencing to determine degree of methylation at four cytosine residues of the promoter (-1439, -1420, -1224, -253). We found that the percent methylation at site -1224 after correction for age trended towards a positive correlation with total BIS-11 scores in cocaine users, but not healthy controls. Percent methylation at site -1420 negatively correlated with rates of delay discounting in healthy controls, but not cocaine users. Lastly, the percent methylation at site -253 positively correlated with attentional bias toward cocaine-associated cues. DNA methylation at these cytosine residues of the promoter may be differentially associated with impulsivity or cocaine-associated environmental cues. Taken together, these data suggest that methylation of the may contribute to individual differences in relapse-related behaviors in CUD.
可卡因使用障碍（CUD）患者在禁欲期间的复吸往往会因高冲动性（倾向于对刺激做出快速的无计划反应而不顾及负面后果）和高线索反应性（例如，对药物奖励刺激的注意力偏向）而加速。更深入地了解个体生物学差异在多大程度上预测或促进问题行为，可能为临床优化CUD诊断和/或治疗提供机会。临床前证据表明，通过5-羟色胺受体（5-HTR）的5-羟色胺（5-HT）神经传递是这些与复吸相关行为个体差异的驱动因素。5-HTR功能的调节通过多种机制发生，包括该基因的DNA甲基化，这是一种与基因-环境相互作用记忆相关的表观遗传修饰。在本研究中，我们检验了这样一个假设：与健康对照相比，可卡因依赖参与者中该基因的甲基化可能与复吸相关的行为易感性有关。冲动性通过自我报告（巴拉特冲动性量表；BIS-11）和延迟折扣任务进行评估，而线索反应性水平则通过可卡因-词语斯特鲁普任务中的表现来确定。从淋巴细胞中提取基因组DNA，对经亚硫酸氢盐处理的DNA进行焦磷酸测序，以确定该基因启动子四个胞嘧啶残基（-1439、-1420、-1224、-253）处的甲基化程度。我们发现，在对年龄进行校正后，可卡因使用者中-1224位点的甲基化百分比与BIS-11总分呈正相关趋势，而健康对照则不然。-1420位点的甲基化百分比与健康对照中的延迟折扣率呈负相关，而可卡因使用者则不然。最后，-253位点的甲基化百分比与对可卡因相关线索的注意力偏向呈正相关。该基因启动子这些胞嘧啶残基处的DNA甲基化可能与冲动性或可卡因相关的环境线索存在差异关联。综上所述，这些数据表明该基因的甲基化可能导致CUD中与复吸相关行为的个体差异。
