Wnt/β-catenin pathway in the prefrontal cortex is required for cocaine-induced neuroadaptations
Wnt/β-catenin pathway in the prefrontal cortex is required for cocaine-induced neuroadaptations
复制标题
DOI：
10.1111/adb.12377
复制
发表时间：
2017-07-01
影响因子：
3.4
通讯作者：
Pacchioni, Alejandra M.
中科院分区：
文献类型：
--
作者：
Cuesta, Santiago;Severin, Maria J.;Pacchioni, Alejandra M.
行为致敏是一种渐进的和持久的增强运动兴奋剂的影响引起的重复管理的滥用药物。它可以分为两个不同的时间和解剖结构域，称为启动和表达，其特征在于特定的分子和神经化学变化。本研究探讨了Wnt经典途径介导的可卡因致敏诱导的作用。我们发现，β-连环蛋白水平在前额叶皮层（PFC），杏仁核（Amyg）和背侧纹状体（CPu）的动物，显示敏感性下降。相应地，在相同区域中GSK 3 β活性水平增加。此外，在致敏动物的PFC中，核组分中的β-连环蛋白水平、Axin 2和Wnt 7 b的mRNA表达降低。然后，为了证明PFC的变化对于致敏的启动至关重要，我们在每次注射可卡因之前，通过全身性治疗GSK 3 β抑制剂（氯化锂）来挽救β-连环蛋白水平，或者通过脑内输注舒林酸来抑制Wnt/β-连环蛋白通路。正如预期的那样，拯救PFC中的β-连环蛋白水平以及CPu和Amyg阻断可卡因诱导的致敏作用，而完全降低PFC中的β-连环蛋白水平则加剧了它。因此，我们的研究结果证明了Wnt/β-连环蛋白通路作为诱导行为致敏作用所需的神经适应的新作用。
Behavioral sensitization is a progressive and enduring enhancement of the motor stimulant effects elicited by repeated administration of drugs of abuse. It can be divided into two distinct temporal and anatomical domains, termed initiation and expression, which are characterized by specific molecular and neurochemical changes. This study examines the role of the Wnt canonical pathway mediating the induction of cocaine sensitization. We found that beta-catenin levels in the prefrontal cortex (PFC), amygdala (Amyg) and dorsal striatum (CPu) are decreased in animals that show sensitization. Accordingly, GSK3 beta activity levels are increased in the same areas. Moreover, beta-catenin levels in nuclear fraction, mRNA expression of Axin2 and Wnt7b are decreased in the PFC of sensitized animals. Then, in order to demonstrate that changes in the PFC are crucial for initiation of sensitization, we either rescue beta-catenin levels with a systemic treatment of a GSK3 beta inhibitor (Lithium Chloride) or inhibit Wnt/beta-catenin pathway with an intracerebral infusion of Sulindac before each cocaine injection. As expected, rescuing beta-catenin levels in the PFC as well as CPu and Amyg blocks cocaine-induced sensitization, while decreasing beta-catenin levels exclusively in the PFC exacerbates it. Therefore, our results demonstrate a new role for the Wnt/beta-catenin pathway as a required neuroadaptation in inducing behavioral sensitization.