Hall F S, Sora I, Uhl G R
Molecular Neurobiology Branch, Intramural Researcch Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
Psychopharmacology (Berl). 2001 Feb;154(1):43-9. doi: 10.1007/s002130000622.
Differences in mu-opiate receptor (MOR) gene expression may modulate the rewarding effects of ethanol.
The effects of MOR gene knockout (KO) were examined in wild-type (+/+), heterozygote MOR KO (+/-), and homozygote MOR KO (-/-) mice on voluntary ethanol consumption, conditioned place preference produced by ethanol, and locomotor responses to ethanol in separate groups of mice.
Voluntary ethanol consumption (2-32% v/v) was examined in a two-bottle home-cage consumption test. The conditioned place preference paradigm was a biased design. Mice received four pairings of ethanol (2.0 g/kg IP) on the initially preferred side and four pairings on the initially non-preferred side with saline. The difference in time spent on the initially non-preferred side (pre- versus post-conditioning) was the measure of drug-induced preference. After habituation to a novel locomotor test chamber mice were tested, on subsequent sessions, for ethanol induced locomotion (0.0, 0.5, 1.0, and 2.0 g/kg IP).
Heterozygous and homozygous MOR KO mice consumed less ethanol than wild-type mice. These effects appeared to be greater in female KO mice than in male KO mice. MOR KO mice, especially females, exhibited less ethanol reward in a conditioned place preference paradigm. These effects on ethanol reward were produced by reductions in MOR expression levels as small as 50%. MOR KO mice exhibited less ethanol-stimulated locomotion than did wild-type mice, an effect that was also largest in females.
These data fit with the reported therapeutic efficacy of MOR antagonists in the treatment of human alcoholism. Allelic variants that confer differing levels of MOR expression could provide different degrees of risk for alcoholism.
μ-阿片受体（MOR）基因表达的差异可能会调节乙醇的奖赏效应。
在野生型（+/+）、杂合子MOR基因敲除（+/−）和纯合子MOR基因敲除（−/−）小鼠中，分别研究MOR基因敲除对自愿乙醇摄入量、乙醇诱导的条件性位置偏爱以及乙醇对运动反应的影响。
在双瓶笼内自愿摄入试验中检测自愿乙醇摄入量（2%-32% v/v）。条件性位置偏爱范式采用有偏设计。小鼠在最初偏爱的一侧接受4次乙醇（2.0 g/kg腹腔注射）配对，在最初不偏爱的一侧接受4次生理盐水配对。在最初不偏爱的一侧（条件化前与条件化后）停留时间的差异作为药物诱导偏爱的指标。在适应新的运动测试箱后，对小鼠进行后续测试，检测乙醇诱导的运动（0.0、0.5、1.0和2.0 g/kg腹腔注射）。
杂合子和纯合子MOR基因敲除小鼠的乙醇摄入量低于野生型小鼠。这些效应在雌性基因敲除小鼠中似乎比雄性基因敲除小鼠中更明显。在条件性位置偏爱范式中，MOR基因敲除小鼠，尤其是雌性小鼠，表现出较低的乙醇奖赏效应。MOR表达水平降低至50%时就会产生这些对乙醇奖赏的影响。MOR基因敲除小鼠比野生型小鼠表现出更低的乙醇刺激运动，这种效应在雌性小鼠中也最为明显。
这些数据与MOR拮抗剂在治疗人类酒精中毒方面的报道疗效相符。赋予不同水平MOR表达的等位基因变体可能为酒精中毒提供不同程度的风险。
