4.7 Article

Independent of differences in taste, B6N mice consume less alcohol than genetically similar B6J mice, and exhibit opposite polarity modulation of tonic GABAAR currents by alcohol

期刊

NEUROPHARMACOLOGY
卷 206, 期 -, 页码 -

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2021.108934

关键词

Alcohol use disorder; Genetic predilection; GABA; Cerebellum; nNOS

资金

  1. National Institute on Alcohol Abuse and Alcoholism Grant [R01AA026078]
  2. Washington State University, Alcohol & Drug Abuse Program intramural grant

向作者/读者索取更多资源

Genetic differences in cerebellar sensitivity to alcohol influence alcohol consumption phenotype in animal models, with alcohol affecting GABA(A)R currents differently in different genotypes, influenced by nNOS expression levels.
Genetic differences in cerebellar sensitivity to alcohol (EtOH) influence EtOH consumption phenotype in animal models and contribute to risk for developing an alcohol use disorder in humans. We previously determined that EtOH enhances cerebellar granule cell (GC) tonic GABA(A)R currents in low EtOH consuming rodent genotypes, but suppresses it in high EtOH consuming rodent genotypes. Moreover, pharmacologically counteracting EtOH suppression of GC tonic GABA(A)R currents reduces EtOH consumption in high alcohol consuming C57BL/6J (B6J) mice, suggesting a causative role. In the low EtOH consuming rodent models tested to date, EtOH enhancement of GC tonic GABA(A)R currents is mediated by inhibition of neuronal nitric oxide synthase (nNOS) which drives increased vesicular GABA release onto GCs and a consequent enhancement of tonic GABA(A)R currents. Consequently, genetic variation in nNOS expression across rodent genotypes is a key determinant of whether EtOH enhances or suppresses tonic GABA(A)R currents, and thus EtOH consumption. We used behavioral, electrophysiological, and immunocytochemical techniques to further explore the relationship between EtOH consumption and GC GABA(A)R current responses in C57BL/6N (B6N) mice. B6N mice consume significantly less EtOH and achieve significantly lower blood EtOH concentrations than B6J mice, an outcome not mediated by differences in taste. In voltage-clamped GCs, EtOH enhanced the GC tonic current in B6N mice but suppressed it in B6J mice. Immunohistochemical and electrophysiological studies revealed significantly higher nNOS expression and function in the GC layer of B6N mice compared to B6Js. Collectively, our data demonstrate that despite being genetically similar, B6N mice consume significantly less EtOH than B6J mice, a behavioral difference paralleled by increased cerebellar nNOS expression and opposite EtOH action on GC tonic GABAAR currents in each genotype.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据