Bilbao Ainhoa, Parkitna Jan Rodriguez, Engblom David, Perreau-Lenz Stéphanie, Sanchis-Segura Carles, Schneider Miriam, Konopka Witold, Westphal Magdalena, Breen Gerome, Desrivieres Sylvane, Klugmann Matthias, Guindalini Camila, Vallada Homero, Laranjeira Ronaldo, de Fonseca Fernando Rodriguez, Schumann Gunter, Schütz Günther, Spanagel Rainer
Department of Psychopharmacology, Central Institute of Mental Health, J5, 68159 Mannheim, Germany.
Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17549-54. doi: 10.1073/pnas.0803959105. Epub 2008 Nov 10.
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.
成瘾的持续性与纹状体和伏隔核（NAc）内神经元的活动诱导可塑性有关。为了确定导致这些适应性变化的分子过程，我们利用Cre/loxP介导的基因敲除技术，敲除了两个对活动做出反应的关键基因表达调节因子，即钙/钙调蛋白依赖性蛋白激酶IV（CaMKIV）及其假定的主要靶点——环磷酸腺苷反应元件结合蛋白（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缺失的影响。在行为水平上，多巴胺感受神经元中缺乏CaMKIV的小鼠对可卡因的敏感性增加，表现为运动敏化增强、条件性位置偏爱增加以及消退后复吸增强。然而，前脑CREB的缺失对这些行为均无影响，尽管它显著减弱了急性可卡因诱导的转录。为了测试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启动子中的一个单核苷酸多态性与可卡因成瘾显著相关，而CREB启动子区域的变异与药物滥用无关。这些发现揭示了CaMKIV在可卡因诱导行为的发展和持续过程中的关键作用，其作用机制与对基因表达和CREB依赖性转录的急性影响无关。
