The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption
The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption
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DOI：
10.1523/jneurosci.3786-05.2006
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发表时间：
2006-02-01
影响因子：
5.3
通讯作者：
Ron, D
中科院分区：
文献类型：
--
作者：
Jeanblanc, J;He, DY;Ron, D
我们最近发现了一种抑制乙醇摄入的稳态途径。这种保护途径由支架蛋白RACK 1和脑源性神经营养因子（BDNF）组成。在神经元暴露于乙醇后，RACK 1易位至细胞核并增加BDNF的表达（McGough等人，2004年）。我们还发现，通过全身施用表达为Tat融合蛋白的RACK 1（Tat-RACK 1）来增加BDNF的水平减少了乙醇消耗，而BDNF水平的降低增强了这种行为（McGough等人，2004年）。基于这些结果，我们假设BDNF受体TrkB的激活对于BDNF对乙醇摄入的影响是必要的，并且BDNF下游的基因产物负调节乙醇消耗。在这里，我们表明，BDNF受体TrkB的抑制增加自愿乙醇消耗野生型小鼠，但不是在小鼠缺乏一个副本的BDNF基因（BDNF+/-）。我们还发现，由乙醇或RACK 1介导的BDNF水平的增加，通过激活TrkB受体，导致背侧纹状体多巴胺D-3受体（D3 R）（BDNF下游基因）水平的增加。最后，我们表明，Tat-RACK 1介导的减少乙醇消耗量的衰减与Trk抑制剂K252 a或多巴胺D3 R偏好拮抗剂U-99194 A [5，6-二甲氧基-2-（二正丙基氨基）茚]共注射，这表明通过RACK 1激活BDNF通路导致多巴胺D3 R的表达增加，这反过来又介导了乙醇消耗量的衰减。
We recently identified a homeostatic pathway that inhibits ethanol intake. This protective pathway consists of the scaffolding protein RACK1 and brain-derived neurotrophic factor (BDNF). RACK1 translocates to the nucleus after exposure of neurons to ethanol and increases expression of BDNF (McGough et al., 2004). We also found that increasing the levels of BDNF via systemic administration of RACK1 expressed as a Tat-fusion protein (Tat-RACK1) reduces ethanol consumption, whereas reduction of BDNF levels augments this behavior (McGough et al., 2004). Based on these results, we hypothesized that activation of the BDNF receptor TrkB is necessary for the effects of BDNF on ethanol intake and that gene products downstream of BDNF negatively regulate ethanol consumption. Here, we show that inhibition of the BDNF receptor TrkB increases voluntary ethanol consumption in wild-type mice but not in mice lacking one copy of the BDNF gene (BDNF+/-). We also find that increases in the levels of BDNF, mediated by ethanol or RACK1, lead to increased dorsal striatal levels of the dopamine D-3 receptor (D3R), a gene downstream of BDNF, via activation of the TrkB receptor. Finally, we show that the Tat-RACK1-mediated reduction of ethanol consumption is attenuated by coinjection with either the Trk inhibitor K252a or the dopamine D3R-prefering antagonist U-99194A [5,6-dimethoxy-2-(di-n-propylamino)indan], suggesting that activation of the BDNF pathway via RACK1 leads to increased expression of the dopamine D3R, which in turn mediates the attenuation of ethanol consumption.