Glial cell line-derived neurotrophic factor reverses alcohol-induced allostasis of the mesolimbic dopaminergic system: implications for alcohol reward and seeking.
Glial cell line-derived neurotrophic factor reverses alcohol-induced allostasis of the mesolimbic dopaminergic system: implications for alcohol reward and seeking.
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DOI：
10.1523/jneurosci.1750-11.2011
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发表时间：
2011-07-06
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影响因子：
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通讯作者：
Ron D
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作者：
Barak S;Carnicella S;Yowell QV;Ron D
我们先前表明，注入胶质细胞源性神经营养因子（GDNF）到腹侧被盖区（VTA）迅速减少酒精摄入量和复发，并增加多巴胺（DA）水平在酒精幼稚大鼠的延髓核（NAc）。戒断过量饮酒与NAc DA水平降低相关，而药物诱导的NAc DA水平升高与奖赏相关。因此，我们测试是否GDNF在腹侧被盖区逆转酒精戒断相关的DA缺乏症和/或具有奖励性质。训练大鼠7周，使其在2瓶选择程序中间歇性地摄入20%的酒精，以消耗高水平的酒精（5.47 ± 0.37 g/kg/24小时）。使用体内微透析，我们表明，24小时退出酒精导致NAc DA溢出大幅减少，这是由内VTA GDNF输注逆转。使用条件性位置偏爱（CPP）范式，我们观察到GDNF本身不诱导CPP，这表明生长因子不是奖励性的。GDNF可阻断酒精CPP的获得和表达。此外，GDNF诱导的剂量-反应曲线向下移动的操作性自我管理的酒精，进一步表明，GDNF抑制，而不是替代，酒精的强化作用。我们的研究结果表明，GDNF通过逆转中脑边缘系统中酒精诱导的变稳态DA缺乏来减少饮酒行为。此外，由于GDNF缺乏滥用倾向，该研究进一步强调GDNF是治疗酒精使用/滥用障碍的有希望的靶点。
We previously showed that infusion of glial cell line-derived neurotrophic factor (GDNF) into the ventral tegmental area (VTA) rapidly reduces alcohol intake and relapse, and increases dopamine (DA) levels in the nucleus accumbens (NAc) of alcohol-naïve rats. Withdrawal from excessive alcohol intake is associated with a reduction in NAc DA levels, whereas drug-induced increases in NAc DA levels are associated with reward. We therefore tested whether GDNF in the VTA reverses alcohol withdrawal-associated DA deficiency and/or possesses rewarding properties. Rats were trained for 7 weeks to consume high levels of alcohol (5.47 ± 0.37 g/kg/24-hrs) in intermittent access to 20% alcohol in a 2-bottle choice procedure. Using in vivo microdialysis, we show that 24-hrs withdrawal from alcohol causes a substantial reduction in NAc DA overflow, which was reversed by intra-VTA GDNF infusion. Using conditioned place preference (CPP) paradigm, we observed that GDNF on its own does not induce CPP, suggesting that the growth factor is not rewarding. However, GDNF blocked acquisition and expression of alcohol-CPP. In addition, GDNF induced a downward shift in the dose-response curve for operant self-administration of alcohol, further suggesting that GDNF suppresses, rather than substitutes for, the reinforcing effects of alcohol. Our findings suggest that GDNF reduces alcohol-drinking behaviors by reversing an alcohol-induced allostatic DA deficiency in the mesolimbic system. In addition, as it lacks abuse liability, the study further highlights GDNF as a promising target for treatment of alcohol use/abuse disorders.