Positive autoregulation of GDNF levels in the ventral tegmental area mediates long-lasting inhibition of excessive alcohol consumption.
Positive autoregulation of GDNF levels in the ventral tegmental area mediates long-lasting inhibition of excessive alcohol consumption.
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DOI：
10.1038/tp.2011.57
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发表时间：
2011
影响因子：
6.8
通讯作者：
Ron D
中科院分区：
文献类型：
--
作者：
Barak S;Ahmadiantehrani S;Kharazia V;Ron D
胶质细胞源性神经营养因子(GDNF)是中脑多巴胺能神经元生存和维持所必需的生长因子。在表达GDNF受体的腹侧被盖区(VTA)激活GDNF通路，对大鼠过度饮酒产生长期的抑制作用。以前在DA能样细胞SHSY5Y上进行的研究表明，GDNF正向调节自己的表达，导致GDNF信号通路的长期激活。在这里，我们确定了GDNF是否在VTA内激活了体内的正自动调节反馈回路，如果是的话，这一机制是否构成了生长因子对过度饮酒的长期抑制作用。我们发现，将重组的胶质细胞源性神经营养因子(rGDNF10 μg)单次注入大鼠的视网膜区，可引起局部GDNFm RNA和蛋白水平的持续升高，这依赖于多肽的从头转录和翻译。重要的是，我们报道了GDNF介导的正自动调节反馈环解释了GDNF在VTA中对过度饮酒的长期抑制作用。具体地说，当蛋白质合成被抑制时，向VTA内注入一次rGDNF对过度饮酒的长期抑制作用被阻止，以及当GDNF表达上调时，使用短发夹状RNA局部击倒VTA中的GDNF mRNA。我们的结果可能对GDNF在包括药物成瘾、慢性应激和帕金森氏症在内的疾病中发挥有益作用的长期治疗的开发具有指导意义。
Glial cell line-derived neurotrophic factor (GDNF) is an essential growth factor for the survival and maintenance of the midbrain dopaminergic (DA-ergic) neurons. Activation of the GDNF pathway in the ventral tegmental area (VTA), where the GDNF receptors are expressed, produces a long-lasting suppression of excessive alcohol consumption in rats. Previous studies conducted in the DA-ergic-like cells, SHSY5Y, revealed that GDNF positively regulates its own expression, leading to a long-lasting activation of the GDNF signaling pathway. Here we determined whether GDNF activates a positive autoregulatory feedback loop in vivo within the VTA, and if so, whether this mechanism underlies the long-lasting suppressive effects of the growth factor on excessive alcohol consumption. We found that a single infusion of recombinant GDNF (rGDNF; 10 μg) into the VTA induces a long-lasting local increase in GDNF mRNA and protein levels, which depends upon de novo transcription and translation of the polypeptide. Importantly, we report that the GDNF-mediated positive autoregulatory feedback loop accounts for the long-lasting inhibitory actions of GDNF in the VTA on excessive alcohol consumption. Specifically, the long-lasting suppressive effects of a single rGDNF infusion into the VTA on excessive alcohol consumption were prevented when protein synthesis was inhibited, as well as when the upregulation of GDNF expression was prevented using short hairpin RNA to focally knock down GDNF mRNA in the VTA. Our results could have implications for the development of long-lasting treatments for disorders in which GDNF has a beneficial role, including drug addiction, chronic stress and Parkinson's disease.
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影响因子：
10.6
作者：
Carnicella, Sebastien;Ahmadiantehrani, Somayeh;He, Dao-Yao;Nielsen, Carsten K.;Bartlett, Selena E.;Janak, Patricia H.;Ron, Dorit
通讯作者：
Ron, Dorit
影响因子：
3.4
作者：
Carnicella, Sebastien;He, Dao-Yao;Ron, Dorit
通讯作者：
Ron, Dorit
影响因子：
2.9
作者：
Lapchak, PA;Jiao, SS;Miller, PJ
通讯作者：
Miller, PJ
影响因子：
4.4
作者：
Mundel, S;Grünblatt, E;Youdim, MBH
通讯作者：
Youdim, MBH
影响因子：
56.9
作者：
LIN, LFH;DOHERTY, DH;COLLINS, F
通讯作者：
COLLINS, F