Profound alteration in reward processing due to a human polymorphism in CHRNA5: a role in alcohol dependence and feeding behavior
Profound alteration in reward processing due to a human polymorphism in CHRNA5: a role in alcohol dependence and feeding behavior
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DOI：
10.1038/s41386-019-0462-0
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发表时间：
2019-10-01
影响因子：
7.6
通讯作者：
Maskos, Uwe
中科院分区：
文献类型：
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作者：
Besson, Morgane;Forget, Benoit;Maskos, Uwe
烟碱受体基因簇 CHRNA5/A3/B4 的人类遗传变异，特别是非同义且频繁的 CHRNA5 变异 rs16969968 (a5SNP)，对人类吸烟行为具有重要影响。许多遗传关联研究还表明 CHRNA5 基因与其他药物成瘾以及体重指数 (BMI) 有关。在这里，我们在转基因大鼠系中对 a5SNP 进行建模，并确定其在酒精依赖和进食行为中的作用。表达 a5SNP 的老鼠会消耗更多的酒精，并在戒酒后表现出更多的酒精复发。这种高复发表型反映在岛叶活动的改变上，与内感受有关，如使用 c-Fos 免疫染色所确定的。类似地，转基因组大鼠的觅食复发率增加，而尼古丁治疗则减少了转基因大鼠和对照大鼠的复发率。这些发现指出了这种人类多态性在奖励处理和除吸烟以外的多种成瘾中的普遍作用。这可能为使用针对烟碱受体的药物治疗酒精使用和饮食失调以及吸烟者的共病铺平道路。
Human genetic variation in the nicotinic receptor gene cluster CHRNA5/A3/B4, in particular the non-synonymous and frequent CHRNA5 variant rs16969968 (a5SNP), has an important consequence on smoking behavior in humans. A number of genetic association studies have additionally implicated the CHRNA5 gene in addictions to other drugs, and also body mass index (BMI). Here, we model the a5SNP, in a transgenic rat line, and establish its role in alcohol dependence, and feeding behavior. Rats expressing the a5SNP consume more alcohol, and exhibit increased relapse to alcohol seeking after abstinence. This high-relapsing phenotype is reflected in altered activity in the insula, linked to interoception, as established using c-Fos immunostaining. Similarly, relapse to food seeking is increased in the transgenic group, while a nicotine treatment reduces relapse in both transgenic and control rats. These findings point to a general role of this human polymorphism in reward processing, and multiple addictions other than smoking. This could pave the way for the use of medication targeting the nicotinic receptor in the treatment of alcohol use and eating disorders, and comorbid conditions in smokers.