Institute of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
Laboratory of Developmental Neuropharmacology, University of North Carolina School of Medicine, Department of Neurology, Chapel Hill, North Carolina.
Biol Psychiatry. 2015 May 15;77(10):850-8. doi: 10.1016/j.biopsych.2014.08.021. Epub 2014 Sep 8.
It has been proposed that therapeutic responses to naltrexone in alcoholism are moderated by variation at the mu-opioid receptor gene locus (OPRM1). This remains controversial because human results vary and no prospectively genotyped studies have been reported. We generated humanized mice carrying the respective human OPRM1 A118G alleles. Here, we used this model system to examine the role of OPRM1 A118G variation for opioid antagonist effects on alcohol responses.
Effects of naltrexone on alcohol reward were examined using intracranial self-stimulation. Effects of naltrexone or nalmefene on alcohol intake were examined in continuous access home cage two-bottle free-choice drinking and operant alcohol self-administration paradigms.
Alcohol lowered brain stimulation reward thresholds in 118GG mice in a manner characteristic of rewarding drugs, and this effect was blocked by naltrexone. Brain stimulation reward thresholds were unchanged by alcohol or naltrexone in 118AA mice. In the home cage, increased alcohol intake emerged in 118GG mice with increasing alcohol concentrations and was 33% higher at 17% alcohol. At this concentration, naltrexone selectively suppressed alcohol intake in 118GG animals to a level virtually identical to that of 118AA mice. No effect of naltrexone was found in the latter group. Similarly, both naltrexone and nalmefene were more effective in suppressing operant alcohol self-administration in 118GG mice.
In a model that allows close experimental control, OPRM1 A118G variation robustly moderates effects of opioid antagonism on alcohol reward and consumption. These findings strongly support a personalized medicine approach to alcoholism treatment that takes into account OPRM1 genotype.
有人提出，阿片受体基因座（OPRM1）的 mu 阿片受体基因变异调节了酒精中毒患者对纳曲酮的治疗反应。这一观点仍存在争议，因为人类的研究结果各不相同，而且没有报道过前瞻性基因分型研究。我们构建了携带相应人类 OPRM1 A118G 等位基因的人源化小鼠。在此，我们使用该模型系统研究了 OPRM1 A118G 变异对阿片受体拮抗剂对酒精反应的影响。
使用颅内自我刺激来检测纳曲酮对酒精奖赏的影响。在连续的自由选择双瓶饮酒和操作性酒精自我给药范式中，检测纳曲酮或纳美芬对酒精摄入的影响。
酒精以有别于奖赏药物的方式降低了 118GG 小鼠的脑刺激奖赏阈值，而这种作用被纳曲酮阻断。118AA 小鼠的酒精或纳曲酮对脑刺激奖赏阈值没有影响。在家庭笼中，118GG 小鼠的酒精摄入量随着酒精浓度的增加而增加，在 17%酒精浓度下增加了 33%。在该浓度下，纳曲酮选择性地抑制了 118GG 动物的酒精摄入量，使其降至与 118AA 小鼠几乎相同的水平。在后一组中没有发现纳曲酮的作用。同样，纳曲酮和纳美芬在抑制 118GG 小鼠的操作性酒精自我给药方面都更有效。
在一个允许进行密切实验控制的模型中，OPRM1 A118G 变异强烈调节了阿片受体拮抗剂对酒精奖赏和消耗的影响。这些发现强烈支持了一种个体化医学方法来治疗酒精中毒，该方法考虑了 OPRM1 基因型。
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