Contet Candice, Kim Airee, Le David, Iyengar Siddharth K, Kotzebue Roxanne W, Yuan Clara J, Kieffer Brigitte L, Mandyam Chitra D
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
Addict Biol. 2014 Sep;19(5):770-80. doi: 10.1111/adb.12040. Epub 2013 Mar 6.
Ethanol exposure and withdrawal alter the generation of new neurons in the adult hippocampus. The endogenous opioid system, particularly the μ-opioid receptor (MOR), can modulate neural progenitors and also plays a critical role in ethanol drinking and dependence. In the present study, we sought to determine whether MOR contributes to the effects of ethanol on the dentate gyrus (DG) neurogenic niche. MOR wild-type (WT), heterozygous (Het) and knockout (KO) littermates were subjected to voluntary ethanol drinking in repeated limited-access two-bottle choice (2BC) sessions. MOR deficiency did not alter progenitor proliferation, neuronal differentiation and maturation, apoptosis or microglia in ethanol-naïve mice. When exposed to five consecutive weeks of 2BC, MOR mutant mice exhibited a gene-dosage-dependent reduction of ethanol consumption compared with WT mice. Introducing a week of ethanol deprivation between each week of 2BC increased ethanol consumption in all genotypes and produced equivalent intakes in WT, Het and KO mice. Under the latter paradigm, ethanol drinking decreased progenitor proliferation and neuronal differentiation in the DG of WT mice. Interestingly, WT mice exhibited a strong negative correlation between ethanol intake and proliferation, which was disrupted in Het and KO mice. Moreover, MOR deficiency blocked the effect of ethanol on neuronal differentiation. MOR deficiency also protected against the neuroimmune response to ethanol drinking. Finally, chronic binge drinking induced a paradoxical decrease in apoptosis, which was independent of MOR. Altogether, our data suggest that MOR is implicated in some of the neuroplastic changes produced by chronic ethanol exposure in the DG.
乙醇暴露和戒断会改变成年海马体中新神经元的生成。内源性阿片系统，尤其是μ-阿片受体（MOR），可以调节神经祖细胞，并且在乙醇饮用和依赖中也起着关键作用。在本研究中，我们试图确定MOR是否参与乙醇对齿状回（DG）神经源性微环境的影响。将MOR野生型（WT）、杂合子（Het）和敲除（KO）的同窝小鼠在重复的有限接触双瓶选择（2BC）实验中进行自愿乙醇饮用。在未接触乙醇的小鼠中，MOR缺乏并未改变祖细胞增殖、神经元分化和成熟、细胞凋亡或小胶质细胞。当连续五周进行2BC实验时，与WT小鼠相比，MOR突变小鼠表现出基因剂量依赖性的乙醇消耗量减少。在每一周的2BC实验之间引入一周的乙醇剥夺，增加了所有基因型小鼠的乙醇消耗量，并且WT、Het和KO小鼠的摄入量相当。在后一种实验模式下，乙醇饮用降低了WT小鼠DG中的祖细胞增殖和神经元分化。有趣的是，WT小鼠的乙醇摄入量与增殖之间呈现出强烈的负相关，而在Het和KO小鼠中这种相关性被破坏。此外，MOR缺乏阻断了乙醇对神经元分化的影响。MOR缺乏还能保护机体免受乙醇饮用引起的神经免疫反应。最后，慢性暴饮诱导了细胞凋亡的反常减少，这与MOR无关。总之，我们的数据表明MOR参与了慢性乙醇暴露在DG中产生的一些神经可塑性变化。
