Monoamine metabolism and behavioral responses to ethanol in mitochondrial aldehyde dehydrogenase knockout mice
Monoamine metabolism and behavioral responses to ethanol in mitochondrial aldehyde dehydrogenase knockout mice
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DOI：
10.1111/j.1530-0277.2006.00200.x
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发表时间：
2006-10-01
影响因子：
3.2
通讯作者：
Strong, Randy
中科院分区：
文献类型：
--
作者：
Fernandez, Elizabeth;Koek, Wouter;Strong, Randy
背景：人们普遍认为，除了去除乙醇代谢过程中产生的乙醛外，线粒体醛脱氢酶（ALDH2）还在单胺多巴胺（DA）和血清素（5-HT）的醛代谢物转化为酸性代谢物的途径中发挥作用。此外，用于治疗酒精中毒的 ALDH2 抑制剂的研究表明，其抗解酒作用可能与抑制单胺代谢有关。因此，我们检验了这样的假设：大脑单胺代谢的改变与 ALDH2 对乙醇行为反应的影响有关。 方法：小鼠产生时带有 ALDH2 基因的基因陷阱突变。 ALDH2-/- 小鼠中不存在 ALDH2 mRNA。肝脏线粒体的蛋白质印迹分析证实 ALDH2-/- 小鼠体内不存在 ALDH2 蛋白。测试了野生型和 ALDH2 缺陷型小鼠不同剂量的乙醇对运动活动、共济失调和 2 瓶乙醇-水偏好测试的影响。结果：野生型和 ALDH2+/- 小鼠更喜欢乙醇而不是水。然而，ALDH2-/- 小鼠比野生型或 ALDH2+/- 小鼠饮用的乙醇明显更少。与野生型或 ALDH2+/- 小鼠相比，ALDH2-/- 小鼠的运动活动和共济失调更明显受到乙醇的影响。通过 HPLCec 测量，基因型对几个大脑区域的 5-HT、DA 或其前体或代谢物的水平没有影响。结论：结果表明：（1）突变基因型对乙醇行为反应的影响与改变的脑单胺代谢无关；（2）体内脑单胺代谢不需要 ALDH2。
Background: It is widely accepted that, in addition to removing acetaldehyde produced during the metabolism of ethanol, mitochondrial aldehyde dehydrogenase (ALDH2) functions in the pathway by which aldehyde metabolites of the monoamines dopamine (DA) and serotonin (5-HT) are converted to their acidic metabolites. Moreover, studies of ALDH2 inhibitors used for treating alcoholism suggest that their antidipsotropic effects may be related to inhibition of monoamine metabolism. Therefore, we examined the hypothesis that altered brain monoamine metabolism is related to the influence of ALDH2 on behavioral responses to ethanol.Methods: Mice were generated with a gene-trap mutation of the ALDH2 gene. ALDH2 mRNA was absent in ALDH2-/- mice. Western blot analysis of liver mitochondria confirmed the absence of ALDH2 protein in the ALDH2-/- mice. Wild-type and ALDH2-deficient mice were tested for the effects of different doses of ethanol on locomotor activity, ataxia, and a 2-bottle ethanol-water preference test.Results: Wild-type and ALDH2+/- mice preferred ethanol to water. However, ALDH2-/- mice drank significantly less ethanol than wild-type or ALDH2+/- mice. Locomotor activity and ataxia were significantly more affected by ethanol in ALDH2-/- mice than in wild-type or ALDH2+/- mice. There was no effect of genotype on levels of 5-HT, DA, or their precursors or metabolites in several brain regions, as measured by HPLCec.Conclusions: The results indicate that: (1) the effect of the mutant genotype on behavioral responses to ethanol is unrelated to altered brain monoamine metabolism and (2) ALDH2 is not required for the metabolism of brain monoamines in vivo.