Activation of alpha4* nAChRs is necessary and sufficient for varenicline-induced reduction of alcohol consumption.
Activation of alpha4* nAChRs is necessary and sufficient for varenicline-induced reduction of alcohol consumption.
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DOI：
10.1523/jneurosci.2601-10.2010
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发表时间：
2010-07-28
期刊：
影响因子：
--
通讯作者：
Tapper AR
中科院分区：
文献类型：
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作者：
Hendrickson LM;Zhao-Shea R;Pang X;Gardner PD;Tapper AR
最近，戒烟治疗varenicline，烟碱乙酰胆碱受体（nAChR）的部分激动剂，已被证明可以减少饮酒。然而，涉及的机制和nAChR亚型尚不清楚。在这里，我们证明伐尼克兰和酒精暴露，无论是单独或组合，选择性激活多巴胺能（DA能）神经元内的后部，但不是前部，腹侧被盖区（VTA）。为了深入了解哪些nAChR亚型可能参与对酒精的反应，我们分析了后腹侧被盖区DA能神经元中nAChR亚单位基因的表达。与未激活的神经元相比，乙醇激活的DA能神经元表达更高水平的α4、α6和β3亚基基因。为了研究含有α4亚基的烟碱受体（α4* nAChRs）在伐伦克林诱导的酒精消耗减少中的作用，我们在两个互补的小鼠模型中研究了药物的作用，一个是不表达α4亚基的敲除系（α4 KO），另一个是表达对激动剂过敏的α4* nAChRs的系（Leu 9 ′Ala）。伐尼克兰（0.1 - 0.3mg/kg，i. p.）在野生型（WT）小鼠中降低2%和20%的酒精消耗量，但在α4 KO动物中未显著降低消耗量。相反，低剂量的伐尼克兰（0.0125 - 0.05mg/kg，i. p.）在WT小鼠中几乎没有效果，显著降低了Leu 9 ′fAla小鼠的乙醇摄入量。将伐尼克兰输注到后腹侧被盖区，而不是前腹侧被盖区，足以减少酒精消耗。总之，我们的数据表明，α4* nAChR的激活对于伐尼克兰减少酒精消耗是必要且充分的。
Recently, the smoking cessation therapeutic varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to reduce alcohol consumption. However, the mechanism and nAChR subtype(s) involved are unknown. Here we demonstrate that varenicline and alcohol exposure, either alone or in combination, selectively activates dopaminergic (DAergic) neurons within the posterior, but not the anterior, ventral tegmental area (VTA). To gain insight into which nAChR subtypes may be involved in the response to alcohol, we analyzed nAChR subunit gene expression in posterior VTA DAergic neurons. Ethanol-activated DAergic neurons expressed higher levels of α4, α6, and β3 subunit genes compared to non-activated neurons. To examine the role of nicotinic receptors containing the α4 subunit (α4* nAChRs) in varenicline-induced reduction of alcohol consumption, we examined the effect of the drug in two complementary mouse models, a knockout line that does not express the α4 subunit (α4 KO) and another line that expresses α4* nAChRs hypersensitive to agonist (Leu9′Ala). While varenicline (0.1 – 0.3 mg/kg, i.p.) reduced 2 % and 20 % alcohol consumption in wildtype (WT) mice, the drug did not significantly reduce consumption in α4 KO animals. Conversely, low doses of varenicline (0.0125 – 0.05 mg/kg, i.p.) that had little effect in WT mice dramatically reduced ethanol intake in Leu9′fAla mice. Infusion of varenicline into the posterior, but not the anterior VTA was sufficient to reduce alcohol consumption. Together, our data indicate that activation of α4* nAChRs is necessary and sufficient for varenicline reduction of alcohol consumption.