Institute of Psychiatry, Medical University of South Carolina, 67 President St., Charleston, SC 29425, USA.
Alcohol Clin Exp Res. 2012 Nov;36(11):2000-7. doi: 10.1111/j.1530-0277.2012.01807.x. Epub 2012 May 2.
Naltrexone is moderately effective for the treatment of alcohol dependence, but there is great individual variability. The opioid receptor (OPRM1) single nucleotide polymorphism (SNP) asn40asp has been shown to alter alcohol and naltrexone response in animals and humans. In addition, the brain opioid and dopamine systems interact and might underlie drinking and craving. This study investigated the effects of the OPRM1 SNP and dopamine transporter (DAT) variable number of tandem repeat (VNTR) genetic differences on drinking, alcohol effects, and naltrexone response under controlled conditions in nontreatment-seeking alcoholics.
Two hundred and sixty-five nontreatment-seeking individuals with alcohol dependence were genotyped a priori for the OPRM1 asn40asp SNP and post hoc for DAT (SLC6A3) 9 and 10 VNTRs. Asp40 carriers (n = 43) and matched asn40 homozygotes (n = 40) were randomized to naltrexone or placebo for 7 days before receiving a priming drink and limited-access alcohol consumption in a bar-lab setting. Effects of genotypes on natural drinking as well as drinking, alcohol effects, and response to naltrexone in the bar-lab setting were examined by genotype.
There were no significant main effects of naltrexone or OPRM1 genotype, or any medication by OPRM1 interaction, on drinking variables. However, in individuals who had at least one DAT 9 VNTR, and who were also OPRM1 asn40 homozygotes, naltrexone reduced drinks/d consumed under natural conditions (p = 0.006), but not in the bar-lab. OPRM1 asn40 homozygotes (p = 0.028) and DAT 9 VNTR carriers (p = 0.032) had more stimulation to alcohol after the priming drink.
This study does not support a salient role for the OPRM1 asp40 alone in predicting drinking or naltrexone effects. However, although exploratory and in need of replication, it introduces the possibility that epistasis between the OPRM1 gene and DAT gene might need to be taken into account when examining differential genetic response to alcohol or medication treatment, especially in early-stage alcoholics.
纳曲酮对酒精依赖症的治疗效果中等，但个体差异较大。阿片受体（OPRM1）单核苷酸多态性（SNP）asn40asp 已被证明会改变动物和人类对酒精和纳曲酮的反应。此外，脑阿片系统和多巴胺系统相互作用，可能是饮酒和渴求的基础。本研究在非治疗性寻求酒精者中，在受控条件下，调查了 OPRM1 SNP 和多巴胺转运体（DAT）可变数串联重复（VNTR）遗传差异对饮酒、酒精作用和纳曲酮反应的影响。
对 265 名非治疗性寻求酒精者进行了 OPRM1 asn40asp SNP 的预先基因分型，以及 DAT（SLC6A3）9 和 10 VNTR 的事后基因分型。将 43 名 Asp40 携带者（n=43）和匹配的 asn40 纯合子（n=40）随机分为纳曲酮或安慰剂组，在酒吧实验室环境中接受诱导性饮料和有限摄入酒精的治疗，为期 7 天。通过基因分型来检查基因型对自然饮酒、酒吧实验室环境中饮酒、酒精作用和纳曲酮反应的影响。
纳曲酮或 OPRM1 基因型、药物与 OPRM1 相互作用均无显著主效应，影响饮酒变量。然而，在至少携带一个 DAT 9 VNTR 且为 OPRM1 asn40 纯合子的个体中，纳曲酮降低了自然条件下的饮酒量（p=0.006），但在酒吧实验室中则没有。OPRM1 asn40 纯合子（p=0.028）和 DAT 9 VNTR 携带者（p=0.032）在接受诱导性饮料后对酒精的刺激作用更大。
本研究不支持 OPRM1 asp40 单独预测饮酒或纳曲酮疗效的重要作用。然而，尽管这是一项探索性研究，需要进一步验证，但它提出了一种可能性，即 OPRM1 基因和 DAT 基因之间的上位性可能需要在研究酒精或药物治疗的遗传反应差异时考虑，特别是在早期酒精者中。
