Giannotti Giuseppe, Caffino Lucia, Calabrese Francesca, Racagni Giorgio, Riva Marco A, Fumagalli Fabio
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy.
Int J Neuropsychopharmacol. 2014 Apr;17(4):625-34. doi: 10.1017/S1461145713001454. Epub 2013 Dec 18.
Although evidence exists that chronic cocaine exposure during adulthood is associated with changes in BDNF expression, whether and how cocaine exposure during adolescence modulates BDNF is still unknown. To address this issue, we exposed rats to repeated cocaine injections from post-natal day (PD) 28 to PD 42, a period that roughly approximates adolescence in humans, and we carried out a detailed analysis of the BDNF system in the medial prefrontal cortex (mPFC) of rats sacrificed 3 d (PD 45) and 48 d (PD 90) after the last cocaine treatment. We found that developmental exposure to cocaine altered transcriptional and translational mechanisms governing neurotrophin expression. Total BDNF mRNA levels, in fact, were enhanced in the mPFC of PD 90 rats exposed to cocaine in adolescence, an effect sustained by changes in BDNF exon IV through the transcription factors CaRF and NF-kB. While a profound reduction of specific BDNF-related miRNAs (let7d, miR124 and miR132) may contribute to explaining the increased proBDNF levels, the up-regulation of the extracellular proteases tPA is indicative of increased processing leading to higher levels of released mBDNF. These changes were associated with increased activation of the trkB-Akt pathway resulting in enhanced pmTOR and pS6 kinase, which ultimately produced an up-regulation of Arc and a consequent reduction of GluA1 expression in the mPFC of PD 90 cocaine-treated rats. These findings demonstrate that developmental exposure to cocaine dynamically dysregulates BDNF and its signaling network in the mPFC of adult rats, providing novel mechanisms that may contribute to cocaine-induced changes in synaptic plasticity.
虽然有证据表明成年期长期接触可卡因与脑源性神经营养因子（BDNF）表达的变化有关，但青少年期接触可卡因是否以及如何调节BDNF仍不清楚。为了解决这个问题，我们从出生后第28天（PD28）到第42天对大鼠进行重复可卡因注射，这一时期大致相当于人类的青春期，并且在最后一次可卡因处理后3天（PD45）和48天（PD90）处死大鼠，对其内侧前额叶皮质（mPFC）中的BDNF系统进行了详细分析。我们发现，发育期接触可卡因会改变调控神经营养因子表达的转录和翻译机制。事实上，青春期接触可卡因的PD90大鼠的mPFC中，BDNF的总mRNA水平升高，这一效应是由BDNF外显子IV通过转录因子CaRF和NF-kB的变化所维持的。虽然特定的BDNF相关微小RNA（let7d、miR124和miR132）的显著减少可能有助于解释前体BDNF水平的升高，但细胞外蛋白酶tPA的上调表明加工增加，导致释放的成熟BDNF水平升高。这些变化与trkB-Akt途径的激活增加有关，导致磷酸化哺乳动物雷帕霉素靶蛋白（pmTOR）和磷酸化核糖体蛋白S6激酶（pS6激酶）增强，最终导致PD90可卡因处理大鼠的mPFC中Arc上调，GluA1表达随之减少。这些发现表明，发育期接触可卡因会动态失调成年大鼠mPFC中的BDNF及其信号网络，提供了可能导致可卡因诱导的突触可塑性变化的新机制。
