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首页> 外文期刊>Addiction biology >Glial cell line-derived neurotrophic factor (GDNF) is an endogenous protector in the mesolimbic system against excessive alcohol consumption and relapse
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Glial cell line-derived neurotrophic factor (GDNF) is an endogenous protector in the mesolimbic system against excessive alcohol consumption and relapse

机译：胶质细胞源性神经营养因子（GDNF）是中脑边缘系统中的内源性保护因子，可防止过量饮酒和复发

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摘要

Moderate social consumption of alcohol is common; however, only a small percentage of individuals transit from social to excessive, uncontrolled alcohol drinking. This suggests the existence of protective mechanisms that prevent the development of alcohol addiction. Here, we tested the hypothesis that the glial cell line-derived neurotrophic factor (GDNF) in the mesolimbic system [e.g. the nucleus accumbens (Acb) and ventral tegmental area (VTA)] is part of such a mechanism. We found that GDNF knockdown, by infecting rat Acb neurons with a small hairpin RNA (shRNA) targeting the GDNF gene, produced a rapid escalation to excessive alcohol consumption and enhanced relapse to alcohol drinking. Conversely, viral-mediated overexpression of the growth factor in the mesolimbic system blocked the escalation from moderate to excessive alcohol drinking. To access the mechanism underlying GDNF's actions, we measured the firing rate of dopaminergic (DAergic) neurons in the VTA after a history of excessive alcohol intake with or without elevating GDNF levels. We found that the spontaneous firing rate of DAergic neurons in the VTA was reduced during alcohol withdrawal and that GDNF reversed this alcohol-induced DA deficiency. Together, our results suggest that endogenous GDNF in the mesolimbic system controls the transition from moderate to excessive alcohol drinking and relapse via reversal of alcohol-dependent neuro-adaptations in DAergic VTA neurons. The development of excessive, uncontrolled alcohol consumption is limited to a small percentage of individuals, suggesting that endogenous mechanisms may prevent alcohol addiction. We tested whether GDNF, a potent inhibitor of alcohol drinking and relapse, comprises one such mechanism. We found that perturbations in endogenous mesolimbic GDNF levels were negatively correlated with the amount of alcohol consumption. GDNF also reversed the long-term suppressive effects of alcohol on dopaminergic activity, indicating that endogenous GDNF gates excessive drinking by alleviating alcohol-induced neuroadaptations.
机译：适度的社会性饮酒很普遍;但是，只有一小部分人从社交转变为过度，不受控制的饮酒。这表明存在防止酒精成瘾发展的保护性机制。在这里，我们测试了以下假设：中脑边缘系统中神经胶质细胞系的神经营养因子（GDNF）[伏隔核（Acb）和腹侧被盖区（VTA）]就是这种机制的一部分。我们发现，通过用靶向GDNF基因的小发夹RNA（shRNA）感染大鼠Acb神经元，GDNF敲低产生了迅速升级为过量饮酒并增强了饮酒复发的趋势。相反，病毒介导的中脑边缘系统中生长因子的过度表达阻止了从中度饮酒到过量饮酒的升级。为了了解GDNF动作的潜在机制，我们测量了在酒精摄入过多或未升高GDNF的情况下，VTA中多巴胺能（DAergic）神经元的放电速率。我们发现，在戒酒期间，VTA中DA能神经元的自发放电率降低，而GDNF逆转了这种酒精诱导的DA缺乏。在一起，我们的结果表明，中脑边缘系统中的内源性GDNF通过逆转DAergic VTA神经元中依赖酒精的神经适应来控制从中度饮酒过渡到过量饮酒和复发的过程。过量，不受控制的酒精消费的发展仅限于一小部分人，这表明内源性机制可以预防酒精成瘾。我们测试了GDNF（一种有效的饮酒和复发抑制剂）是否包含一种这样的机制。我们发现内源性中胚层GDNF水平的摄动与饮酒量呈负相关。 GDNF还逆转了酒精对多巴胺能活性的长期抑制作用，表明内源性GDNF通过减轻酒精引起的神经适应来控制过量饮酒。

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