Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Michael E. DeBakey V.A. Medical Center, Houston, TX, USA.
Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Michael E. DeBakey V.A. Medical Center, Houston, TX, USA; South Central Mental Illness, Research, Education and Clinical Center (MIRECC), Houston, TX, USA.
Behav Brain Res. 2022 Feb 10;418:113675. doi: 10.1016/j.bbr.2021.113675. Epub 2021 Nov 16.
Genetic variation in the serotonin transporter (SLC6A4) has been shown to moderate the acute subjective effects of cocaine. Methylation of the SLC6A4 gene is associated with decreased transcription of the serotonin transporter, leading to increased serotonin in the synapse. In this study, methylation of the SLC6A4 gene was investigated in the moderation of the subjective effects of cocaine. Non-treatment-seeking cocaine-dependent individuals (N = 53) were intravenously administered cocaine (40 mg) and saline in a randomized order. The subjective effects of cocaine were self-reported using a visual analog scale starting prior to the administration of cocaine (-15 min) or saline and up to 20 min after infusion. Participants were evaluated for methylation of the SLC6A4 promoter region and 5-HTTLPR genotype. A series of ANCOVAs for SLC6A4 methylation (high/low) were run for each of ten subjective and three cardiovascular effects controlling for age, sex [utilizing the sex-determining region Y protein (SRY)], and population structure (determined from ancestry informative markers and STRUCTURE software). Participants with SLC6A4 hypermethylation reported greater subjective response to cocaine for 'depressed' relative to participants with SLC6A4 hypomethylation (experiment-wise p = 0.002). These findings indicate that SLC6A4 methylation moderates the 'depressed' subjective effect of cocaine in non-treatment-seeking cocaine-dependent participants.
基因变异在 5-羟色胺转运体（SLC6A4）中已经被证明可以调节可卡因的急性主观效应。SLC6A4 基因的甲基化与 5-羟色胺转运体的转录减少有关，导致突触中 5-羟色胺增加。在这项研究中，研究了 SLC6A4 基因的甲基化在调节可卡因的主观效应中的作用。非治疗寻求可卡因依赖者（N=53）按随机顺序静脉给予可卡因（40mg）和生理盐水。使用视觉模拟量表在给予可卡因（-15 分钟）或生理盐水之前开始自我报告可卡因的主观效应，并在输注后 20 分钟内进行报告。评估了 SLC6A4 启动子区域的甲基化和 5-HTTLPR 基因型。针对 SLC6A4 甲基化（高/低）进行了一系列 ANCOVA 分析，针对十种主观和三种心血管效应进行了分析，控制了年龄、性别[利用性别决定区域 Y 蛋白（SRY）]和人口结构（从祖先信息标记和 STRUCTURE 软件确定）。与 SLC6A4 低甲基化的参与者相比，SLC6A4 高甲基化的参与者报告对可卡因的“抑郁”主观反应更大（实验性 p=0.002）。这些发现表明，SLC6A4 甲基化调节了非治疗寻求可卡因依赖者中可卡因的“抑郁”主观效应。
