αCaMKII controls the establishment of cocaine's reinforcing effects in mice and humans.
αCaMKII controls the establishment of cocaine's reinforcing effects in mice and humans.
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DOI：
10.1038/tp.2014.97
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发表时间：
2014-10-07
影响因子：
6.8
通讯作者：
Müller CP
中科院分区：
文献类型：
--
作者：
Easton AC;Lourdusamy A;Havranek M;Mizuno K;Solati J;Golub Y;Clarke TK;Vallada H;Laranjeira R;Desrivières S;Moll GH;Mössner R;Kornhuber J;Schumann G;Giese KP;Fernandes C;Quednow BB;Müller CP
虽然有相当多的可卡因经常使用者会上瘾，但可卡因依赖的分子危险因素仍然未知。认为药物使用和记忆形成可能有共同的分子和解剖学途径。α - ca2 +/钙调素依赖性蛋白激酶ii （αCaMKII）是学习和记忆的关键介质，也参与药物相关的可塑性。α - camkii的自磷酸化被证明可以加速学习。因此，我们研究了αCaMKII自磷酸化在小鼠可卡因使用相关行为建立过程中的作用。我们发现αCaMKII自磷酸化缺陷的αCaMKIIT286A小鼠表现出条件位置偏好的延迟建立，但对可卡因（20 mg kg−1，腹腔注射）的急性行为激活、致敏或条理性过度运动没有变化。体内微透析显示，αCaMKIIT286A小鼠急性给药（20 mg kg - 1，腹腔注射）后，伏隔核（NAcc）和前额皮质的多巴胺（DA）和5-羟色胺（5-HT）反应减弱，而去甲肾上腺素反应保留。在可卡因作用下，αCaMKIIT286A小鼠的DA和5-HT活性减弱后，NAcc中c-Fos活性受损。为了将啮齿动物的研究结果应用于人类，在巴西（n=688）和瑞士（n=141）两个独立的可卡因使用者样本中，对几种CAMK2A基因多态性进行了测试，以确定它们对可卡因依赖的快速建立风险。对两个样本的荟萃分析证实，CAMK2A rs3776823 tt等位基因携带者比c等位基因携带者更快地过渡到严重的可卡因使用。综上所述，这些数据表明αCaMKII控制着可卡因强化效应形成的速度。
Although addiction develops in a considerable number of regular cocaine users, molecular risk factors for cocaine dependence are still unknown. It was proposed that establishing drug use and memory formation might share molecular and anatomical pathways. Alpha-Ca2+/calmodulin-dependent protein kinase-II (αCaMKII) is a key mediator of learning and memory also involved in drug-related plasticity. The autophosphorylation of αCaMKII was shown to accelerate learning. Thus, we investigated the role of αCaMKII autophosphorylation in the time course of establishing cocaine use-related behavior in mice. We found that αCaMKII autophosphorylation-deficient αCaMKIIT286A mice show delayed establishment of conditioned place preference, but no changes in acute behavioral activation, sensitization or conditioned hyperlocomotion to cocaine (20 mg kg−1, intraperitoneal). In vivo microdialysis revealed that αCaMKIIT286A mice have blunted dopamine (DA) and blocked serotonin (5-HT) responses in the nucleus accumbens (NAcc) and prefrontal cortex after acute cocaine administration (20 mg kg−1, intraperitoneal), whereas noradrenaline responses were preserved. Under cocaine, the attenuated DA and 5-HT activation in αCaMKIIT286A mice was followed by impaired c-Fos activation in the NAcc. To translate the rodent findings to human conditions, several CAMK2A gene polymorphisms were tested regarding their risk for a fast establishment of cocaine dependence in two independent samples of regular cocaine users from Brazil (n=688) and Switzerland (n=141). A meta-analysis across both samples confirmed that CAMK2A rs3776823 TT-allele carriers display a faster transition to severe cocaine use than C-allele carriers. Together, these data suggest that αCaMKII controls the speed for the establishment of cocaine's reinforcing effects.
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影响因子：
6.9
作者：
Glantz, M. D.;Anthony, J. C.;Berglund, P. A.;Degenhardt, L.;Dierker, L.;Kalaydjian, A.;Merikangas, K. R.;Ruscio, A. M.;Swendsens, J.;Kessler, R. C.
通讯作者：
Kessler, R. C.
影响因子：
4.4
作者：
Abdalla, Renata Rigacci;Madruga, Clarice S.;Laranjeira, Ronaldo
通讯作者：
Laranjeira, Ronaldo
影响因子：
4.7
作者：
Easton, Alanna C.;Lucchesi, Walter;Fernandes, Cathy
通讯作者：
Fernandes, Cathy
影响因子：
6.9
作者：
Hulka, L. M.;Eisenegger, C.;Quednow, B. B.
通讯作者：
Quednow, B. B.
影响因子：
56.9
作者：
Gabriel, SB;Schaffner, SF;Altshuler, D
通讯作者：
Altshuler, D