Increased ethanol drinking in "humanized" mice expressing the mu opioid receptor A118G polymorphism are mediated through sex-specific mechanisms.
Increased ethanol drinking in "humanized" mice expressing the mu opioid receptor A118G polymorphism are mediated through sex-specific mechanisms.
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DOI：
10.1016/j.brainresbull.2017.07.017
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发表时间：
2018-04
影响因子：
3.8
通讯作者：
Morgan DJ
中科院分区：
文献类型：
--
作者：
Henderson-Redmond AN;Lowe TE;Tian XB;Morgan DJ
μ阿片受体基因（Oprm 1）的A118 G单核苷酸多态性（SNP）与调节酒精的奖励效应有关。临床和临床前研究表明，G等位基因可能赋予酒精依赖的遗传易感性，尽管这些影响是否具有性别特异性仍然未知。我们使用“人源化”118 AA或118 GG等位基因纯合的雄性和雌性小鼠，以确定A118 G SNP是否以性别特异性方式在两瓶选择和黑暗中饮用（DID）范例中增强乙醇消耗。还评估了小鼠对纳洛酮敏感性的差异，通过条件性位置偏好（CPP）评估的乙醇奖励，以及使用旋转杆和翻正反射（LORR）试验对乙醇的镇静/共济失调作用的敏感性。我们发现，男性和女性118 GG小鼠喝了显着更多的乙醇比118 AA同窝使用连续访问，两瓶选择范例。在限制进入的DID饮酒模型中，（i）雌性（而非雄性）118 GG小鼠比118 AA小鼠消耗更多的乙醇，（ii）纳洛酮预处理在减弱118 AA和118 GG雌性小鼠的乙醇摄入方面同样有效，而在雄性小鼠中没有效果。雄性和雌性118 GG和雌性118 AA小鼠对乙醇产生了强烈的条件性位置偏好（CPP）。与雌性118 AA小鼠相比，雌性118 GG小鼠在旋转杆和LORR试验中对乙醇的镇静/共济失调作用的敏感性较低，而雄性小鼠在任一试验中的反应均无差异。我们的研究结果表明，增加酒精消费在雄性118 GG小鼠可能是由于增加乙醇奖励，而增加饮酒在雌性118 GG小鼠可能是由于敏感性降低的镇静/共济失调作用的乙醇。总的来说，这些数据可以用来帮助确定性别特异性药物治疗，以打击酒精使用障碍。
The A118G single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (Oprm1) has been implicated in mediating the rewarding effects of alcohol. Clinical and preclinical studies suggest that the G allele may confer a genetic vulnerability to alcohol dependence, though it remains unknown whether these effects are sex-specific. We used male and female mice homozygous for the “humanized” 118AA or 118GG alleles to determine whether the A118G SNP potentiates ethanol consumption in a sex-specific manner in both the two-bottle choice and drinking-in-the-dark (DID) paradigms. Mice were also assessed for differences in naltrexone sensitivity, ethanol reward assessed via conditioned place preference (CPP), and sensitivity to the sedative/ataxic effects of ethanol using the rota-rod and loss of righting reflex (LORR) assays. We found that male and female 118GG mice drank significantly more ethanol than 118AA littermates using a continuous access, two-bottle choice paradigm. In the limited-access DID drinking model, (i) female (but not male) 118GG mice consumed more ethanol than 118AA mice and (ii) naltrexone pretreatment was equally efficacious at attenuating ethanol intake in both 118AA and 118GG female mice while having no effect in males. Male and female 118GG and female 118AA mice developed a robust conditioned place preference (CPP) for ethanol. Female 118GG mice displayed less sensitivity to the sedative/ataxic effects of ethanol compared to female 118AA mice on both the rota-rod and the LORR assays while male mice did not differ in their responses on either assay. Our findings suggest that increased ethanol consumption in male 118GG mice may be due to increased ethanol reward, while increased drinking in female 118GG mice might be due to decreased sensitivity to the sedative/ataxic effects of ethanol. Collectively, these data might be used to help identify sex-specific pharmacotherapies to combat alcohol use disorders.
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影响因子：
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作者：
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通讯作者：
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发表时间：
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