McGeary John E, Monti Peter M, Rohsenow Damaris J, Tidey Jennifer, Swift Robert, Miranda Robert
Center for Alcohol and Addiction Studies, Brown University, Providence, Rhode Island 02906, USA.
Alcohol Clin Exp Res. 2006 Aug;30(8):1288-96. doi: 10.1111/j.1530-0277.2006.00156.x.
Naltrexone (NTX) reduces drinking and craving in alcoholic individuals in treatment and also in heavy drinkers. Polymorphisms in the D4 dopamine receptor (DRD4) gene and mu-opiate receptor gene (OPRM1) may moderate NTX's effects on craving. This study examined these candidate genes as moderators of the effects of NTX on cue-elicited urge to drink in non-treatment-seeking heavy drinkers.
Data from the subset of 93 participants who consented for genetic testing in a larger study of medication effects were used to examine pharmacogenetic hypotheses. The non-treatment-seeking male and female heavy drinkers (62% alcohol dependent) were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene [L=7 or more (n=34), S=less than 7 (n=56)] and Asn40Asp single-nucleotide polymorphism in the OPRM1 gene [29 aspartate (Asp) carriers and 59 asparagine (Asn) homozygotes]. Ten days after randomization to NTX (50 mg) or placebo, participants completed an alcohol cue reactivity assessment.
Any medication effects were all accounted for by interaction with genotype. Naltrexone increased urge for alcohol in Asp carriers across alcohol and neutral beverage cue trials and had no effect on homozygous Asn carriers. Asp40 carriers on either medication had greater decreases (from resting baseline) in mean arterial blood pressure across all beverage cue trials compared with Asn carriers. For DRD4, no differential medication effects by DRD4 polymorphism were found. Alcohol dependence diagnosis did not moderate the effects of gene and medication on cue-elicited measures.
The differential responses to NTX due to variation in the OPRM1 gene may help explain conflicting results in clinical trials and suggest directions for patient-treatment matching.
纳曲酮（NTX）可减少接受治疗的酗酒者以及重度饮酒者的饮酒量和酒瘾。多巴胺D4受体（DRD4）基因和μ-阿片受体基因（OPRM1）的多态性可能会调节NTX对酒瘾的影响。本研究将这些候选基因作为NTX对未寻求治疗的重度饮酒者线索诱发的饮酒冲动影响的调节因素进行了研究。
在一项关于药物作用的大型研究中，选取了93名同意进行基因检测的参与者的数据来检验药物遗传学假设。对未寻求治疗的男性和女性重度饮酒者（62%为酒精依赖者）进行DRD4基因可变串联重复多态性（L=7或更多，n=34；S=少于7，n=56）以及OPRM1基因Asn40Asp单核苷酸多态性（29名天冬氨酸（Asp）携带者和59名天冬酰胺（Asn）纯合子）的基因分型。随机分组接受NTX（50毫克）或安慰剂10天后，参与者完成酒精线索反应性评估。
所有药物作用均由与基因型的相互作用所解释。在酒精和中性饮料线索试验中，纳曲酮增加了Asp携带者对酒精的渴望，而对纯合子Asn携带者没有影响。在所有饮料线索试验中，服用任何一种药物的Asp40携带者与Asn携带者相比，平均动脉血压（相对于静息基线）下降幅度更大。对于DRD4基因，未发现DRD4多态性对药物作用有差异。酒精依赖诊断并未调节基因和药物对线索诱发指标的影响。
由于OPRM1基因变异导致对NTX的不同反应可能有助于解释临床试验中相互矛盾的结果，并为患者与治疗的匹配提供指导方向。
