胶质细胞源性神经营养因子是乙醇介导的奖赏以及戒酒一段时间后的乙醇消耗的内源性负调节因子。
GDNF is an endogenous negative regulator of ethanol-mediated reward and of ethanol consumption after a period of abstinence.
作者信息
Carnicella Sebastien, Ahmadiantehrani Somayeh, Janak Patricia H, Ron Dorit
机构信息
The Ernest Gallo Research Center, University of California-San Francisco, Emeryville, CA 94608, USA.
出版信息
Alcohol Clin Exp Res. 2009 Jun;33(6):1012-24. doi: 10.1111/j.1530-0277.2009.00922.x. Epub 2009 Mar 19.
BACKGROUND
We previously found that activation of the glial cell line-derived neurotrophic factor (GDNF) pathway in the ventral tegmental area (VTA) reduces ethanol-drinking behaviors. In this study, we set out to assess the contribution of endogenous GDNF or its receptor GFRalpha1 to the regulation of ethanol-related behaviors.
METHODS
GDNF and GFRalpha1 heterozygote mice (HET) and their wild-type littermate controls (WT) were used for the studies. Ethanol-induced hyperlocomotion, sensitization, and conditioned place preference (CPP), as well as ethanol consumption before and after a period of abstinence were evaluated. Blood ethanol concentration (BEC) was also measured.
RESULTS
We observed no differences between the GDNF HET and WT mice in the level of locomotor activity or in sensitization to ethanol-induced hyperlocomotion after systemic injection of a nonhypnotic dose of ethanol and in BEC. However, GDNF and GFRalpha1 mice exhibited increased place preference to ethanol as compared with their WT littermates. The levels of voluntary ethanol or quinine consumption were similar in the GDNF HET and WT mice, however, a small but significant increase in saccharin intake was observed in the GDNF HET mice. No changes were detected in voluntary ethanol, saccharin or quinine consumption of GFRalpha1 HET mice as compared with their WT littermates. Interestingly, however, both the GDNF and GFRalpha1 HET mice consumed much larger quantities of ethanol after a period of abstinence from ethanol as compared with their WT littermates. Furthermore, the increase in ethanol consumption after abstinence was found to be specific for ethanol as similar levels of saccharin intake were measured in the GDNF and GFRalpha1 HET and WT mice after abstinence.
CONCLUSIONS
Our results suggest that endogenous GDNF negatively regulates the rewarding effect of ethanol and ethanol-drinking behaviors after a period of abstinence.
背景
我们之前发现，腹侧被盖区（VTA）中胶质细胞源性神经营养因子（GDNF）信号通路的激活可减少乙醇摄入行为。在本研究中，我们着手评估内源性GDNF或其受体GFRalpha1对乙醇相关行为调节的作用。
方法
使用GDNF和GFRalpha1杂合子小鼠（HET）及其野生型同窝对照小鼠（WT）进行研究。评估乙醇诱导的运动亢进、敏化和条件性位置偏爱（CPP），以及禁欲前后的乙醇消耗量。同时测量血液乙醇浓度（BEC）。
结果
我们观察到，在全身注射非催眠剂量的乙醇后，GDNF杂合子小鼠和野生型小鼠在运动活动水平、对乙醇诱导的运动亢进的敏化程度以及BEC方面均无差异。然而，与野生型同窝小鼠相比，GDNF和GFRalpha1杂合子小鼠对乙醇的位置偏爱增加。GDNF杂合子小鼠和野生型小鼠的自愿乙醇或奎宁消耗量相似，然而，GDNF杂合子小鼠的糖精摄入量有小幅但显著的增加。与野生型同窝小鼠相比，GFRalpha1杂合子小鼠的自愿乙醇、糖精或奎宁消耗量未检测到变化。然而，有趣的是，与野生型同窝小鼠相比，GDNF和GFRalpha1杂合子小鼠在戒酒一段时间后摄入的乙醇量要多得多。此外，戒酒后乙醇消耗量的增加被发现是乙醇特有的，因为在戒酒的GDNF和GFRalpha1杂合子小鼠和野生型小鼠中测量到的糖精摄入量水平相似。
结论
我们的结果表明，内源性GDNF对乙醇的奖赏效应和戒酒一段时间后的乙醇摄入行为具有负向调节作用。
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