Tropomyosin-related kinase B in the mesolimbic dopamine system: region-specific effects on cocaine reward.
Tropomyosin-related kinase B in the mesolimbic dopamine system: region-specific effects on cocaine reward.
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DOI：
10.1016/j.biopsych.2008.09.032
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发表时间：
2009-04-15
影响因子：
10.6
通讯作者：
Self, David W.
中科院分区：
文献类型：
--
作者：
Graham, Danielle L.;Krishnan, Vaishnav;Larson, Erin B.;Graham, Ami;Edwards, Scott;Bachtell, Ryan K.;Simmons, Diana;Gent, Lana M.;Berton, Olivier;Bolanos, Carlos A.;DiLeone, Ralph J.;Parada, Luis F.;Nestler, Eric J.;Self, David W.
先前的研究发现，来自伏隔核（NAc）神经元的脑源性神经营养因子（BDNF）可以介导导致可卡因成瘾的持续行为变化。为了进一步研究中脑边缘多巴胺系统中的BDNF信号传导，我们分析了可卡因自我给药3周后大鼠NAc和腹侧被盖区（VTA）中原肌球蛋白相关激酶B（Trk B）信使RNA（mRNA）和蛋白质的变化。为了研究BDNF-TrkB活性在可卡因奖赏中的VTA和NAc中的作用，我们在floxed BDNF和floxed TrkB小鼠中使用局部病毒介导的Cre重组酶表达，以在可卡因位置条件反射测试中敲低VTA和NAc中的BDNF或TrkB，并在可卡因自我给药测试中敲低NAc中的TrkB。我们发现，3周的主动可卡因自我管理显着增加TrkB蛋白水平的NAc壳，而轭（被动）可卡因暴露产生了类似的增加VTA。在任何一个区域的局部BDNF敲低减少可卡因奖励的地方条件反射，而只有TrkB敲低在NAc减少可卡因奖励。在自我施用可卡因的小鼠中，NAc中的TrkB敲低产生可卡因自我施用剂量-反应曲线的下移，但对可卡因或蔗糖自我施用的获得没有影响。总之，这些数据表明，在VTA或NAc神经元中合成的BDNF对于维持对可卡因奖励的敏感性是重要的，但只有NAc中TrkB受体的BDNF激活介导这种效应。此外，长期使用可卡因会上调NAc TrkB，这可能会促进向成瘾程度更高的生物状态的转变。
Previous studies found that brain-derived neurotrophic factor (BDNF) derived from nucleus accumbens (NAc) neurons can mediate persistent behavioral changes that contribute to cocaine addiction. To further investigate BDNF signaling in the mesolimbic dopamine system, we analyzed tropomyosin-related kinase B (TrkB) messenger RNA (mRNA) and protein changes in the NAc and ventral tegmental area (VTA) in rats following 3 weeks of cocaine self-administration. To study the role of BDNF-TrkB activity in the VTA and NAc in cocaine reward, we used localized viral-mediated Cre recombinase expression in floxed BDNF and floxed TrkB mice to knockdown BDNF or TrkB in the VTA and NAc in cocaine place conditioning tests and TrkB in the NAc in cocaine self-administration tests. We found that 3 weeks of active cocaine self-administration significantly increased TrkB protein levels in the NAc shell, while yoked (passive) cocaine exposure produced a similar increase in the VTA. Localized BDNF knockdown in either region reduced cocaine reward in place conditioning, whereas only TrkB knockdown in the NAc reduced cocaine reward. In mice self-administering cocaine, TrkB knockdown in the NAc produced a downward shift in the cocaine self-administration dose-response curve but had no effect on the acquisition of cocaine or sucrose self-administration. Together, these data suggest that BDNF synthesized in either VTA or NAc neurons is important for maintaining sensitivity to cocaine reward but only BDNF activation of TrkB receptors in the NAc mediates this effect. In addition, up-regulation of NAc TrkB with chronic cocaine use could promote the transition to more addicted biological states.
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