Fumagalli Fabio, Bedogni Francesco, Frasca Angelisa, Di Pasquale Laura, Racagni Giorgio, Riva Marco Andrea
Department of Pharmacological Sciences, Center of Neuropharmacology, Via Balzaretti 9, 20133 Milan, Italy.
Mol Pharmacol. 2006 Nov;70(5):1726-34. doi: 10.1124/mol.106.026302. Epub 2006 Aug 14.
We provide evidence that cocaine evokes short- and long-lasting increases in activity-regulated cytoskeletal-associated protein (Arc) expression after a finely tuned, time-dependent and regional-selective expression profile. Acute experiments revealed that cocaine up-regulates Arc expression primarily in striatum and prefrontal cortex through a dopamine D1-dependent mechanism and a combination of D1- and D2-dependent mechanisms, respectively. Aside from cocaine-dependent Arc elevation, we show for the first time that D1 and D2 receptors tonically regulate basal Arc expression following a regional-selective profile. As opposed to the effects of a single cocaine injection on Arc expression, which dissipate within 24 h, subchronic (five daily injections) or chronic (14 daily injections) cocaine administration, with animals sacrificed hours or days after the last treatment, demonstrated that Arc expression is still up-regulated long after treatment cessation, suggesting that adaptive changes have been set in motion by the prolonged administration of the psychostimulant. In summary, our findings are the first to demonstrate that repeated exposure to cocaine leads to long-lasting dysregulation of Arc expression in the corticostriatal network, thus establishing a molecular basis to explain, at least partially, the impaired synaptic transmission caused by cocaine abuse at this level. Furthermore, given the role exerted by Arc in cytoarchitectural rearrangements, it is conceivable to speculate that it mediates changes in synaptic connectivity brought about by cocaine. Our findings thus pinpoint this molecule as a neuropathological underpinning and molecular bridge that connects short- and long-term neuronal modifications associated with cocaine abuse.
我们提供的证据表明，可卡因在呈现出精细调节、时间依赖性和区域选择性的表达模式后，会引起活性调节细胞骨架相关蛋白（Arc）表达的短期和长期增加。急性实验表明，可卡因分别通过多巴胺D1依赖性机制以及D1和D2依赖性机制的组合，主要上调纹状体和前额叶皮质中的Arc表达。除了可卡因依赖性的Arc升高外，我们首次表明D1和D2受体以区域选择性模式对基础Arc表达进行紧张性调节。与单次注射可卡因对Arc表达的影响（在24小时内消散）不同，亚慢性（每日注射五次）或慢性（每日注射14次）可卡因给药，在最后一次治疗后数小时或数天处死动物，结果表明在停止治疗后很长时间Arc表达仍上调，这表明精神兴奋剂的长期给药已引发适应性变化。总之，我们的研究结果首次证明，反复接触可卡因会导致皮质纹状体网络中Arc表达的长期失调，从而至少部分地建立了一个分子基础来解释可卡因滥用在此水平上造成的突触传递受损。此外，鉴于Arc在细胞结构重排中的作用，可以推测它介导了可卡因引起的突触连接变化。因此，我们的研究结果指出该分子是一种神经病理学基础以及分子桥梁，它连接了与可卡因滥用相关的短期和长期神经元修饰。
