Wyatt Letisha R, Finn Deborah A, Khoja Sheraz, Yardley Megan M, Asatryan Liana, Alkana Ronald L, Davies Daryl L
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA, 90033, USA.
Neurochem Res. 2014 Jun;39(6):1127-39. doi: 10.1007/s11064-014-1271-9. Epub 2014 Mar 27.
P2X receptors (P2XRs) are a family of cation-permeable ligand-gated ion channels activated by synaptically released extracellular adenosine 5'-triphosphate. The P2X4 subtype is abundantly expressed in the central nervous system and is sensitive to low intoxicating ethanol concentrations. Genetic meta-analyses identified the p2rx4 gene as a candidate gene for innate alcohol intake and/or preference. The current study used mice lacking the p2rx4 gene (knockout, KO) and wildtype (WT) C57BL/6 controls to test the hypothesis that P2X4Rs contribute to ethanol intake. The early acquisition and early maintenance phases of ethanol intake were measured with three different drinking procedures. Further, we tested the effects of ivermectin (IVM), a drug previously shown to reduce ethanol's effects on P2X4Rs and to reduce ethanol intake and preference, for its ability to differentially alter stable ethanol intake in KO and WT mice. Depending on the procedure and the concentration of the ethanol solution, ethanol intake was transiently increased in P2X4R KO versus WT mice during the acquisition of 24-h and limited access ethanol intake. IVM significantly reduced ethanol intake in P2X4R KO and WT mice, but the degree of reduction was 50 % less in the P2X4R KO mice. Western blot analysis identified significant changes in γ-aminobutyric acidA receptor α1 subunit expression in brain regions associated with the regulation of ethanol behaviors in P2X4R KO mice. These findings add to evidence that P2X4Rs contribute to ethanol intake and indicate that there is a complex interaction between P2X4Rs, ethanol, and other neurotransmitter receptor systems.
P2X受体（P2XRs）是一类阳离子通透的配体门控离子通道家族，由突触释放的细胞外三磷酸腺苷激活。P2X4亚型在中枢神经系统中大量表达，且对低浓度的致醉乙醇敏感。基因荟萃分析确定p2rx4基因为先天酒精摄入量和/或偏好的候选基因。本研究使用缺乏p2rx4基因的小鼠（基因敲除，KO）和野生型（WT）C57BL/6对照小鼠，以检验P2X4受体促成乙醇摄入的假说。采用三种不同的饮水程序测量乙醇摄入的早期获取和早期维持阶段。此外，我们测试了伊维菌素（IVM）的作用，该药物先前已被证明可降低乙醇对P2X4受体的作用，并减少乙醇摄入和偏好，以研究其对KO和WT小鼠稳定乙醇摄入量的差异影响。根据程序和乙醇溶液的浓度，在24小时获取和限量摄入乙醇期间，与WT小鼠相比，P2X4R基因敲除小鼠的乙醇摄入量短暂增加。IVM显著降低了P2X4R基因敲除小鼠和WT小鼠的乙醇摄入量，但在P2X4R基因敲除小鼠中的降低程度少了50%。蛋白质印迹分析确定，在与P2X4R基因敲除小鼠乙醇行为调节相关的脑区中，γ-氨基丁酸A受体α1亚基表达有显著变化。这些发现进一步证明P2X4受体促成乙醇摄入，并表明P2X4受体、乙醇和其他神经递质受体系统之间存在复杂的相互作用。
