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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Loss Of The Ca~(2+)/calmodulin-dependent Protein Kinase Type Iv In Dopaminoceptive Neurons Enhances Behavioral Effects Of Cocaine
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Loss Of The Ca~(2+)/calmodulin-dependent Protein Kinase Type Iv In Dopaminoceptive Neurons Enhances Behavioral Effects Of Cocaine

机译：多巴胺能神经元中Ca〜（2 +）/钙调蛋白依赖性蛋白激酶Iv的丢失增强可卡因的行为作用

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The persistent nature of addiction has been associated with activity-induced plasticity of neurons within the striatum and nucleus accumbens (NAc). To identify the molecular processes leading to these adaptations, we performed Cre/loxP-mediated genetic ablations of two key regulators of gene expression in response to activity, the Ca~(2+)/calmodulin-dependent protein kinase IV (CaMKIV) and its postulated main target, the cAMP-responsive element binding protein (CREB). We found that acute cocaine-induced gene expression in the striatum was largely unaffected by the loss of CaMKIV. On the behavioral level, mice lacking CaMKIV in dopaminoceptive neurons displayed increased sensitivity to cocaine as evidenced by augmented expression of locomotor sensitization and enhanced conditioned place preference and reinstatement after extinction. However, the loss of CREB in the forebrain had no effect on either of these behaviors, even though it robustly blunted acute cocaine-induced transcription. To test the relevance of these observations for addiction in humans, we performed an 'association study of CAMK4 and CREB promoter polymorphisms with cocaine addiction in a large sample of addicts. We found that a single nucleotide polymorphism in the CAMK4 promoter was significantly associated with cocaine addiction, whereas variations in the CREB promoter regions did not correlate with drug abuse. These findings reveal a critical role for CaMKIV in . the development and persistence of cocaine-induced behaviors, through mechanisms dissociated from acute effects on gene expression and CREB-dependent transcription.
机译：成瘾的持续性与活动诱导的纹状体和伏隔核（NAc）中神经元的可塑性有关。为了确定导致这些适应的分子过程，我们对基因表达的两个关键调节因子Ca〜（2 +）/钙调蛋白依赖性蛋白激酶IV（CaMKIV）及其活性进行了Cre / loxP介导的基因表达调控。假定的主要靶标是cAMP反应元件结合蛋白（CREB）。我们发现，急性可卡因诱导的纹状体基因表达在很大程度上不受CaMKIV丢失的影响。在行为水平上，多巴胺感受神经元中缺乏CaMKIV的小鼠表现出对可卡因的敏感性增加，这由运动敏化的表达增强以及灭绝后条件性位置偏好和恢复增强证明。然而，前脑CREB的丢失对这两种行为均没有影响，即使它强烈减弱了可卡因诱导的转录。为了检验这些观察结果与人类成瘾的相关性，我们在大量成瘾者样本中进行了CAMK4和CREB启动子多态性与可卡因成瘾的关联研究。我们发现，CAMK4启动子中的单核苷酸多态性与可卡因成瘾显着相关，而CREB启动子区域中的变异与药物滥用无关。这些发现揭示了CaMKIV在大鼠中的关键作用。通过从对基因表达和CREB依赖的转录的急性影响中分离出来的机制来发展和维持可卡因诱导的行为。

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