Cuesta Santiago, Severin Maria J, Batuecas Jorgelina, Rosso Silvana B, Pacchioni Alejandra M
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
Douglas Mental Health University Institute, Canada.
Addict Biol. 2017 Jul;22(4):933-945. doi: 10.1111/adb.12377. Epub 2016 Feb 22.
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 β-catenin levels in the prefrontal cortex (PFC), amygdala (Amyg) and dorsal striatum (CPu) are decreased in animals that show sensitization. Accordingly, GSK3β activity levels are increased in the same areas. Moreover, β-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 β-catenin levels with a systemic treatment of a GSK3β inhibitor (Lithium Chloride) or inhibit Wnt/β-catenin pathway with an intracerebral infusion of Sulindac before each cocaine injection. As expected, rescuing β-catenin levels in the PFC as well as CPu and Amyg blocks cocaine-induced sensitization, while decreasing β-catenin levels exclusively in the PFC exacerbates it. Therefore, our results demonstrate a new role for the Wnt/β-catenin pathway as a required neuroadaptation in inducing behavioral sensitization.
行为敏化是指反复给予滥用药物所引发的运动刺激效应的渐进性和持久性增强。它可分为两个不同的时间和解剖学领域，即起始和表达，其特征是特定的分子和神经化学变化。本研究考察了Wnt经典通路在介导可卡因敏化诱导中的作用。我们发现，在表现出敏化的动物中，前额叶皮质（PFC）、杏仁核（Amyg）和背侧纹状体（CPu）中的β-连环蛋白水平降低。相应地，相同区域的GSK3β活性水平升高。此外，在敏化动物的PFC中，核组分中的β-连环蛋白水平、Axin2和Wnt7b的mRNA表达降低。然后，为了证明PFC中的变化对敏化起始至关重要，我们要么用GSK3β抑制剂（氯化锂）进行全身治疗来挽救β-连环蛋白水平，要么在每次注射可卡因之前通过脑内注入舒林酸来抑制Wnt/β-连环蛋白通路。正如预期的那样，挽救PFC以及CPu和Amyg中的β-连环蛋白水平可阻断可卡因诱导的敏化，而仅降低PFC中的β-连环蛋白水平则会加剧敏化。因此，我们的结果证明了Wnt/β-连环蛋白通路作为诱导行为敏化所需的神经适应性的新作用。
