Weinshenker D, Rust N C, Miller N S, Palmiter R D
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
J Neurosci. 2000 May 1;20(9):3157-64. doi: 10.1523/JNEUROSCI.20-09-03157.2000.
Although norepinephrine (NE) has been implicated in animal models of ethanol consumption for many years, the exact nature of its influence is not clear. Lesioning and pharmacological studies examining the role of NE in ethanol consumption have yielded conflicting results. We took a genetic approach to determine the effect of NE depletion on ethanol-mediated behaviors by using dopamine beta-hydroxylase knockout (Dbh -/-) mice that specifically lack the ability to synthesize NE. Dbh -/- males have reduced ethanol preference in a two-bottle choice paradigm and show a delay in extinguishing an ethanol-conditioned taste aversion, suggesting that they drink less ethanol in part because they find its effects more aversive. Both male and female Dbh -/- mice are hypersensitive to the sedative and hypothermic effects of systemic ethanol administration, and the sedation phenotype can be rescued pharmacologically by acute replacement of central NE. Neither the decreased body temperature nor changes in ethanol metabolism can explain the differences in consumption and sedation. These results demonstrate a significant role for NE in modulating ethanol-related behaviors and physiological responses.
尽管去甲肾上腺素（NE）多年来一直被认为与动物酒精摄入模型有关，但其影响的确切性质尚不清楚。研究NE在酒精摄入中作用的损伤和药理学研究得出了相互矛盾的结果。我们采用遗传学方法，通过使用特异性缺乏合成NE能力的多巴胺β-羟化酶基因敲除（Dbh-/-）小鼠，来确定NE耗竭对酒精介导行为的影响。Dbh-/-雄性小鼠在双瓶选择范式中对酒精的偏好降低，并且在消除酒精条件性味觉厌恶方面表现出延迟，这表明它们饮用较少酒精部分是因为它们觉得酒精的作用更令人厌恶。雄性和雌性Dbh-/-小鼠对全身给予酒精的镇静和体温过低作用均高度敏感，并且通过急性补充中枢NE可在药理学上挽救镇静表型。体温降低和酒精代谢变化均无法解释酒精摄入和镇静方面的差异。这些结果表明NE在调节与酒精相关的行为和生理反应中起重要作用。
