P2X4 receptors (P2X4Rs) represent a novel target for the development of drugs to prevent and/or treat alcohol use disorders.
P2X4 receptors (P2X4Rs) represent a novel target for the development of drugs to prevent and/or treat alcohol use disorders.
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DOI：
10.3389/fnins.2014.00176
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发表时间：
2014
影响因子：
4.3
通讯作者：
Davies DL
中科院分区：
文献类型：
--
作者：
Franklin KM;Asatryan L;Jakowec MW;Trudell JR;Bell RL;Davies DL
酒精使用障碍（AUD）具有惊人的社会经济影响。可用的治疗选择很少，而且很大程度上是不够的。这些缺点突出表明迫切需要开发有效的药物来预防和/或治疗 AUD。一个关键障碍是缺乏有关乙醇 (EtOH) 发挥其药理活性的分子靶点的信息。本综述重点介绍了 P2X4 受体 (P2X4R) 作为开发治疗 AUD 的疗法的靶标的发现，并讨论了伊维菌素 (IVM) 作为治疗 AUD 的潜在临床工具的用途。 P2XR 是由细胞外 ATP 激活的配体门控离子通道 (LGIC) 家族。在 P2XR 亚型中，P2X4R 在 CNS 中表达最丰富。综合证据表明 P2X4R 参与 AUD 的发生和进展。首先，体外研究报告，药理学相关的 EtOH 浓度可以负向调节 ATP 激活电流。其次，中皮质边缘多巴胺系统中的 P2X4R 被认为在突触可塑性中发挥作用，并且位于调节大脑奖赏系统的理想位置。第三，嗜酒 (P) 大鼠的 p2rx4 基因功能表达低于不嗜酒 (NP) 大鼠，表明酒精摄入量与 P2X4R 表达之间存在反比关系。同样，28 品系大鼠的全脑 p2rx4 表达与先天 24 小时酒精偏好呈负相关。第四，缺乏 p2rx4 基因的小鼠比野生型对照小鼠饮用更多的乙醇。第五，IVM是P2X4Rs的正调节剂，在体外拮抗EtOH介导的P2X4Rs抑制，并减少体内EtOH的摄入和偏好。这些发现表明 P2X4R 有助于乙醇的摄入。本综述总结了最近的研究结果，重点关注 P2X4R 作为 EtOH 作用的分子靶点、其在 EtOH 饮酒行为中的作用以及 IVM 作为 AUD 潜在疗法对其活性的调节。
Alcohol use disorders (AUDs) have a staggering socioeconomic impact. Few therapeutic options are available, and they are largely inadequate. These shortcomings highlight the urgent need to develop effective medications to prevent and/or treat AUDs. A critical barrier is the lack of information regarding the molecular target(s) by which ethanol (EtOH) exerts its pharmacological activity. This review highlights findings implicating P2X4 receptors (P2X4Rs) as a target for the development of therapeutics to treat AUDs and discusses the use of ivermectin (IVM) as a potential clinical tool for treatment of AUDs. P2XRs are a family of ligand-gated ion channels (LGICs) activated by extracellular ATP. Of the P2XR subtypes, P2X4Rs are expressed the most abundantly in the CNS. Converging evidence suggests that P2X4Rs are involved in the development and progression of AUDs. First, in vitro studies report that pharmacologically relevant EtOH concentrations can negatively modulate ATP-activated currents. Second, P2X4Rs in the mesocorticolimbic dopamine system are thought to play a role in synaptic plasticity and are located ideally to modulate brain reward systems. Third, alcohol-preferring (P) rats have lower functional expression of the p2rx4 gene than alcohol-non-preferring (NP) rats suggesting an inverse relationship between alcohol intake and P2X4R expression. Similarly, whole brain p2rx4 expression has been shown to relate inversely to innate 24 h alcohol preference across 28 strains of rats. Fourth, mice lacking the p2rx4 gene drink more EtOH than wildtype controls. Fifth, IVM, a positive modulator of P2X4Rs, antagonizes EtOH-mediated inhibition of P2X4Rs in vitro and reduces EtOH intake and preference in vivo. These findings suggest that P2X4Rs contribute to EtOH intake. The present review summarizes recent findings focusing on the P2X4R as a molecular target of EtOH action, its role in EtOH drinking behavior and modulation of its activity by IVM as a potential therapy for AUDs.
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影响因子：
64.8
作者：
CULLY, DF;VASSILATIS, DK;ARENA, JP
通讯作者：
ARENA, JP
影响因子：
3.3
作者：
D'Ambrosi, N;Murra, B;Volonté, C
通讯作者：
Volonté, C
DOI：
10.1111/j.1460-9568.2011.07763.x
发表时间：
2011-07
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Baxter AW;Choi SJ;Sim JA;North RA
通讯作者：
North RA
影响因子：
11.4
作者：
Buell, G;Lewis, C;Surprenant, A
通讯作者：
Surprenant, A
影响因子：
5.5
作者：
Bouchery, Ellen E.;Harwood, Henrick J.;Brewer, Robert D.
通讯作者：
Brewer, Robert D.