Jeanblanc Jerome, He Dao-Yao, McGough Nancy N H, Logrip Marian L, Phamluong Khanhky, Janak Patricia H, Ron Dorit
Ernest Gallo Research Center, University of California, San Francisco, Emeryville, California 94608, USA.
J Neurosci. 2006 Feb 1;26(5):1457-64. doi: 10.1523/JNEUROSCI.3786-05.2006.
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 D3 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.
我们最近发现了一条抑制乙醇摄入的稳态途径。这条保护途径由支架蛋白RACK1和脑源性神经营养因子（BDNF）组成。神经元暴露于乙醇后，RACK1会转位至细胞核并增加BDNF的表达（麦高夫等人，2004年）。我们还发现，通过全身给予表达为Tat融合蛋白（Tat-RACK1）的RACK1来提高BDNF水平，可减少乙醇消耗，而降低BDNF水平则会增强这种行为（麦高夫等人，2004年）。基于这些结果，我们推测BDNF受体TrkB的激活对于BDNF对乙醇摄入的作用是必要的，并且BDNF下游的基因产物会负向调节乙醇消耗。在此，我们表明抑制BDNF受体TrkB会增加野生型小鼠的自愿乙醇消耗，但不会增加缺乏一个BDNF基因拷贝（BDNF(+/-)）的小鼠的乙醇消耗。我们还发现，由乙醇或RACK1介导的BDNF水平升高，会通过激活TrkB受体导致BDNF下游基因多巴胺D3受体（D3R）的背侧纹状体水平升高。最后，我们表明，与Trk抑制剂K252a或多巴胺D3R选择性拮抗剂U-99194A[5,6-二甲氧基-2-(二正丙基氨基)茚满]共同注射会减弱Tat-RACK1介导的乙醇消耗减少，这表明通过RACK1激活BDNF途径会导致多巴胺D3R表达增加，进而介导乙醇消耗的减少。
