Department of Physiology and Pharmacology, University of Georgia College of Veterinary Medicine, Athens, GA, 30602, USA.
Department of Physiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Sci Rep. 2020 Jul 3;10(1):11017. doi: 10.1038/s41598-020-67291-0.
The previous reports on an addiction vulnerability marker in the human SLC4A7 gene encoding the Na/HCO transporter NBCn1 suggest that this pH-regulating protein may affect alcohol-related behavior and response. Here, we examined alcohol consumption and sensitivity to the sedative effects of alcohol in male NBCn1 knockout mice. These mice displayed lower pH in neurons than wildtype controls, determined by intracellular pH in hippocampal neuronal cultures. Neurons from knockout mice had a higher action potential threshold and a more depolarized membrane potential, thus reducing membrane excitability. In a two-bottle free choice procedure, knockout mice consumed more alcohol than controls and consistently increased alcohol consumption after repeated alcohol deprivation periods. Quinine and sucrose preference was similar between genotypes. Knockout mice showed increased propensity for alcohol-induced conditioned place preference. In loss of righting reflex assessment, knockout mice revealed increased sensitivity to alcohol-induced sedation and developed tolerance to the sedation after repeated alcohol administrations. Furthermore, chronic alcohol consumption caused NBCn1 downregulation in the hippocampus and striatum of mice and humans. These results demonstrate an important role of NBCn1 in regulation of alcohol consumption and sensitivity to alcohol-induced sedation.
先前关于编码 Na/HCO 转运体 NBCn1 的人类 SLC4A7 基因中成瘾易感性标志物的报告表明，这种 pH 调节蛋白可能影响与酒精相关的行为和反应。在这里，我们研究了雄性 NBCn1 敲除小鼠的酒精消耗和对酒精镇静作用的敏感性。通过海马神经元培养物中的细胞内 pH 测定，这些小鼠的神经元 pH 值低于野生型对照。敲除小鼠的神经元动作电位阈值更高，膜电位更去极化，从而降低了膜兴奋性。在双瓶自由选择程序中，敲除小鼠比对照小鼠消耗更多的酒精，并且在反复酒精剥夺期间持续增加酒精消耗。基因型之间的奎宁和蔗糖偏好相似。敲除小鼠表现出增加的酒精诱导条件性位置偏好倾向。在翻正反射丧失评估中，敲除小鼠显示出对酒精诱导镇静作用的敏感性增加，并在反复酒精给药后对镇静作用产生耐受。此外，慢性酒精消费导致小鼠和人类海马体和纹状体中 NBCn1 的下调。这些结果表明 NBCn1 在调节酒精消耗和对酒精诱导镇静作用的敏感性方面起着重要作用。
