Juvenile administration of concomitant methylphenidate and fluoxetine alters behavioral reactivity to reward- and mood-related stimuli and disrupts ventral tegmental area gene expression in adulthood.
Juvenile administration of concomitant methylphenidate and fluoxetine alters behavioral reactivity to reward- and mood-related stimuli and disrupts ventral tegmental area gene expression in adulthood.
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DOI：
10.1523/jneurosci.1470-11.2011
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发表时间：
2011-07-13
期刊：
影响因子：
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通讯作者：
Bolaños-Guzmán CA
中科院分区：
文献类型：
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作者：
Warren BL;Iñiguez SD;Alcantara LF;Wright KN;Parise EM;Weakley SK;Bolaños-Guzmán CA
在儿科人群中，同时使用哌醋甲酯(MPH)和氟西汀(Flx)的情况有所上升。然而，在幼年期联合应用MPH和FLOX(MPH+FLOX)的长期神经生物学后果尚不清楚。我们从出生后第20-35天开始给幼年SD-Dawley雄性大鼠注射生理盐水(VEH)、MPH、FLX或MPH+FLX，并在药物暴露后24小时或2个月评估它们对奖赏和情绪相关刺激的反应。我们还评估了腹侧被盖区(VTA)内的mRNA和蛋白质水平，以确定MPH、Flx或MPH+Flx对细胞外信号调节蛋白激酶-1/2(ERK)途径的影响--ERK是与动机和情绪调节有关的信号级联反应。与VEH治疗的大鼠相比，MPH+Flx增强了对药物(即可卡因)和蔗糖奖励的敏感性，以及焦虑(即升高的正迷宫)和压力(即强迫游泳)引发的情况。与VEH组大鼠相比，MPH+Flx暴露2个月后ERK2及其下游靶基因cAMP反应元件结合蛋白(CREB)、脑源性神经营养因子(BDNF)、CFOS、早期生长反应蛋白1(Zif268)和哺乳动物雷帕霉素靶点(MTOR)的mRNA表达也增加，ERK2、CREB和mTOR的蛋白磷酸化水平也增加。使用单纯疱疹病毒介导的基因转移来阻断VTA内ERK2的活性，我们在药物治疗2个月后挽救了MPH+Flx诱导的强迫游泳任务中的行为缺陷。这些结果表明，青春期前同时暴露MPH+FLX增加了对奖励相关刺激的敏感性，同时增强了对应激情况的敏感性，至少部分原因是VTA内ERK信号的长期中断。
There is a rise in the concurrent use of methylphenidate (MPH) and fluoxetine (FLX) in pediatric populations. However, the long-term neurobiological consequences of combined MPH and FLX treatment (MPH+FLX) during juvenile periods are unknown. We administered saline (VEH), MPH, FLX, or MPH+FLX to juvenile Sprague-Dawley male rats from postnatal day 20–35, and assessed their reactivity to reward- and mood-related stimuli 24-h or 2-months after drug exposure. We also assessed mRNA and protein levels within the ventral tegmental area (VTA) to determine the effect of MPH, FLX, or MPH+FLX on the extracellular signal-regulated protein kinase-1/2 (ERK) pathway – a signaling cascade implicated in motivation and mood regulation. MPH+FLX enhanced sensitivity to drug (i.e., cocaine) and sucrose rewards, as well as anxiety- (i.e., elevated plus-maze) and stress- (i.e., forced swimming) eliciting situations when compared to VEH-treated rats. MPH+FLX exposure also increased mRNA of ERK2 and its downstream targets cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), cFos, early growth response protein-1 (zif268), and mammalian target of rapamycin (mTOR), and also increased protein phosphorylation of ERK2, CREB, and mTOR 2-months after drug exposure when compared to VEH-treated rats. Using herpes simplex virus-mediated gene transfer to block ERK2 activity within the VTA, we rescued the MPH+FLX-induced behavioral deficits seen in the forced swimming task 2-months after drug treatment. These results indicate that concurrent MPH+FLX exposure during preadolescence increases sensitivity to reward-related stimuli while simultaneously enhancing susceptibility to stressful situations, at least in part, due to long-lasting disruptions in ERK signaling within the VTA.