Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol
Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol
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DOI：
10.1096/fj.01-0593com
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发表时间：
2002-01-01
期刊：
影响因子：
4.8
通讯作者：
Heilig, M
中科院分区：
文献类型：
--
作者：
Rimondini, R;Arlinde, C;Heilig, M
大脑长期暴露于乙醇中是产生乙醇依赖的先决条件，但潜在的神经适应尚不清楚。在这里，我们证明，受到反复循环的中毒和戒断的大鼠在自愿乙醇摄入量方面表现出显著和持久的增加。阿坎普罗酸是一种对人类酒精中毒临床有效的化合物，可拮抗暴露诱导但非自发的酒精摄入。扣带皮层和杏仁核的表达分析揭示了该模型中一组长期上调的转录本。这些包括先前与酒精依赖有关的通路成员（谷氨酸能、内源性大麻素和单胺能神经传递），以及以前未被认为与这种疾病有关的通路成员（例如，丝裂原激活的蛋白激酶通路成员）。因此，交替的乙醇中毒和戒断期足以诱导脑功能状态的改变，这可能是通过基因表达的长期变化来编码的。这些观察结果可能对临床如何处理酒精中毒具有重要意义。通过靶向在我们的模型中发现的受调节的基因产物，可能会开发出新的临床有效的治疗方法。
Prolonged exposure of the brain to ethanol is a prerequisite for developing ethanol dependence, but the underlying neural adaptations are unknown. Here we demonstrate that rats subjected to repeated cycles of intoxication and withdrawal develop a marked and long-lasting increase in voluntary ethanol intake. Exposure-induced but not spontaneous alcohol intake is antagonized by acamprosate, a compound clinically effective in human alcoholism. Expression analysis of cingulate cortex and amygdala reveals a set of long-term up-regulated transcripts in this model. These include members of pathways previously implicated in alcohol dependence (glutamatergic, endocannabinoid, and monoaminergic neurotransmission), as well as pathways not previously thought to be involved in this disorder (e. g., members of the mitogen-activated protein kinase pathway). Thus, alternating periods of ethanol intoxication and withdrawal are sufficient to induce an altered functional brain state, which is likely to be encoded by long-term changes in gene expression. These observations may have important implications for how alcoholism is managed clinically. Novel clinically effective treatments may be possible to develop by targeting the products of genes found to be regulated in our model.