Dopamine D3 receptor is necessary for ethanol consumption: an approach with buspirone.
Dopamine D3 receptor is necessary for ethanol consumption: an approach with buspirone.
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DOI：
10.1038/npp.2014.51
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发表时间：
2014-07
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影响因子：
--
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中脑边缘多巴胺(DA)控制药物和酒精的寻求行为，但特定的DA受体亚型的作用尚不清楚。我们验证了D3R基因缺失或D3R药物阻断抑制小鼠酒精偏好的假设。用D3R拮抗剂SB277011A和U99194A处理或不用D3R拮抗剂SB277011A和U99194A处理的D3R缺陷小鼠(D3R−/−)及其野生型(WT)产仔，在长期自由选择饮酒(两瓶选择)和狂欢饮酒范式(在黑暗中饮酒，DID)中进行了测试。通过分子模拟进一步评价了D3R拮抗剂的选择性。D3R−/−的乙醇摄入量可以忽略不计，而WT的酒精摄入量在两瓶选择和DO范例中都可以忽略不计。D3R拮抗剂可抑制WT小鼠的乙醇摄取，但对D3R−/−小鼠无效。乙醇摄入增加了WT和D3R−/−中RACK1和脑源性神经营养因子的表达；WT中D3R也有较强的过表达。因此，与RACK1/BDNF激活相关的D3R表达增加似乎在自愿酒精摄入中起到了强化作用。事实上，TrkB选择性拮抗剂ANA-12阻断了BDNF通路，逆转了长期稳定的乙醇摄入，并强烈减少了纹状体D3R的表达。最后，我们对丁螺环酮进行了评估，丁螺环酮是一种被批准用于治疗焦虑症的药物，具有D3R拮抗剂活性(通过分子模型分析证实)，可以有效地抑制乙醇摄入。因此，通过D3R的DA信号对酒精相关的奖赏和消耗是必不可少的，并可能代表一个新的脱机治疗靶点。
Mesolimbic dopamine (DA) controls drug- and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D3R gene deletion or the D3R pharmacological blockade inhibits ethanol preference in mice. D3R-deficient mice (D3R−/−) and their wild-type (WT) littermates, treated or not with the D3R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D3R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D3R−/− and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D3R antagonists inhibited ethanol intake in WT but was ineffective in D3R−/− mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D3R−/−; in WT there was also a robust overexpression of D3R. Thus, increased expression of D3R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D3R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D3R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D3R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.
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DOI：
10.1017/s1461145712000661
发表时间：
2013-03
期刊：
The international journal of neuropsychopharmacology
影响因子：
--
作者：
Bergman J;Roof RA;Furman CA;Conroy JL;Mello NK;Sibley DR;Skolnick P
通讯作者：
Skolnick P
影响因子：
5.3
作者：
Jeanblanc, J;He, DY;Ron, D
通讯作者：
Ron, D
影响因子：
4.7
作者：
Collo, Ginetta;Bono, Federica;Missale, Cristina
通讯作者：
Missale, Cristina
影响因子：
16.2
作者：
Bowers, M. Scott;Chen, Billy T.;Bonci, Antonello
通讯作者：
Bonci, Antonello
影响因子：
3.2
作者：
Brand, Ines;Fliegel, Sarah;Noori, Hamid R.
通讯作者：
Noori, Hamid R.