Partial agonists of the α3β4* neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats.
Partial agonists of the α3β4* neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats.
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DOI：
10.1038/npp.2010.191
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发表时间：
2011-02
期刊：
影响因子：
--
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文献类型：
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酒精使用障碍(AUD)影响着数百万人，仍然缺乏有效的治疗策略。尽管有证据表明神经型烟碱型乙酰胆碱受体(NAChRs)在AUDS中起作用，但还没有确定nAChR的哪些亚型参与了AUDS。最近的人类遗传关联研究表明，编码α3、α5和β4亚单位的基因簇CHRNA3-CHRNA5-CHRNB4与尼古丁和酒精依赖的易感性有关，但由于缺乏合适和选择性的研究工具，它们在乙醇介导的行为中的作用尚不清楚。为了确定α3和β4亚基在乙醇自我给药中的作用，我们开发和表征了α3β4 nAChRs、CP-601932和PF-4575180的高亲和力部分激动剂。在长期暴露后，CP-601932和PF-4575180都选择性地减少乙醇，但不减少蔗糖消耗和有效的自我给药。我们发现，CP-601932和PF-4575180在α3β4 nAChRs上的功能潜力与它们在大鼠脑内的游离浓度相关，这表明其对乙醇自我给药的影响是通过与α3β4 nAChRs的相互作用而介导的。此外，Varenicline是一种已获批准的戒烟辅助药物，此前已被证明可减少大鼠和小鼠的酒精消耗和寻找，在允许与α3β4 nAChRs功能相互作用的自由脑浓度下减少乙醇摄入量。此外，选择性α4β2*nAChR拮抗剂DHβE不能减少乙醇摄入量。总之，这些数据为人类遗传关联研究提供了进一步的支持，这些研究表明CHRNA3和CHRNB4基因与乙醇介导的行为有关。CP-601932已被证明对人类是安全的，可能代表着一种潜在的治疗AUDS的新方法。
Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the α3, α5 and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the α3, and β4 subunits of the nAChR in ethanol self-administration, we developed and characterized high affinity partial agonists at α3β4 nAChRs, CP-601932 and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with their unbound rat brain concentrations suggesting that the effects on ethanol self-administration are mediated via interaction with α3β4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with α3β4 nAChRs. Furthermore, the selective α4β2* nAChR antagonist, DHβE, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs.
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DOI：
10.2174/187152710790966597
发表时间：
2010-03
期刊：
CNS & neurological disorders drug targets
影响因子：
--
作者：
Chatterjee S;Bartlett SE
通讯作者：
Bartlett SE
DOI：
10.1523/jneurosci.2601-10.2010
发表时间：
2010-07-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hendrickson LM;Zhao-Shea R;Pang X;Gardner PD;Tapper AR
通讯作者：
Tapper AR
DOI：
10.1111/j.1601-183x.2008.00444.x
发表时间：
2009-08
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Kamens HM;McKinnon CS;Li N;Helms ML;Belknap JK;Phillips TJ
通讯作者：
Phillips TJ
影响因子：
4.7
作者：
Fonck, Carlos;Nashmi, Raad;Salas, Ramiro;Zhou, Chunyi;Huang, Qi;De Biasi, Mariella;Lester, Robin A. J.;Lester, Henry A.
通讯作者：
Lester, Henry A.
影响因子：
3.8
作者：
BLOMQVIST, O;SODERPALM, B;ENGEL, JA
通讯作者：
ENGEL, JA