Wiley Matthew D, Poveromo Laura B, Antapasis John, Herrera Carolina M, Bolaños Guzmán Carlos A
Program in Neuroscience, Department of Psychology, Florida State University, Tallahassee, FL 32306-4301, USA.
Neuropsychopharmacology. 2009 Apr;34(5):1339-50. doi: 10.1038/npp.2008.188. Epub 2008 Oct 15.
Methylphenidate (MPH) is commonly prescribed in childhood and adolescence for the treatment of attention-deficit/hyperactivity disorders. In rodents, MPH exposure during preadolescence (postnatal days (PD) 20-35) causes decreased sensitivity to drug and natural rewards, while enhancing a negative emotional state characterized by increased sensitivity to aversive situations later in adulthood. It has been proposed that this behavioral profile may be mediated, at least in part, by changes in the expression of dynorphin, the endogenous ligand for kappa-opioid receptors (KORs). Because increases in dynorphin activity and activation of KOR induce aversive states, we examined the possibility that these behavioral deficits may be mediated by changes in KOR function, and that MPH-exposed rats would demonstrate increased sensitivity to the kappa-agonist U-50488. Sprague-Dawley male rats were treated with MPH (2 mg/kg) or its saline vehicle (VEH) during PD20-35. When adults (PD90+), these rats were divided into groups receiving saline, U-50488 (5 mg/kg), or nor-binaltorphimine (20 mg/kg), a kappa-antagonist, and their behavioral reactivity to various emotion-eliciting stimuli was assessed. Results show that MPH exposure decreases cocaine place conditioning and sucrose preference, while increasing vulnerability to anxiety (elevated plus maze)- and stress (forced swimming)-eliciting situations, and that these behavioral deficits can be intensified by U-50488, while being normalized by nor-binaltorphimine treatment. These results are consistent with the notion that dysregulated dynorphin/kappa-opioid systems may mediate deficits in behavioral responding after developmental MPH exposure. Moreover, these findings further support the idea of kappa-antagonists as potential pharmacotherapy for the treatment of anxiety- and depression-related disorders.
哌甲酯（MPH）常用于儿童和青少年注意力缺陷多动障碍的治疗。在啮齿动物中，青春期前（出生后第20 - 35天）接触MPH会导致对药物和自然奖励的敏感性降低，同时增强一种负面情绪状态，其特征是成年后期对厌恶情境的敏感性增加。有人提出，这种行为特征可能至少部分是由强啡肽（κ-阿片受体（KORs）的内源性配体）表达的变化介导的。由于强啡肽活性增加和KOR激活会诱发厌恶状态，我们研究了这些行为缺陷可能由KOR功能变化介导的可能性，以及接触MPH的大鼠对κ-激动剂U - 50488的敏感性是否会增加。在出生后第20 - 35天，将斯普拉格-道利雄性大鼠用MPH（2mg/kg）或其生理盐水载体（VEH）进行处理。成年后（出生后第90天及以后），将这些大鼠分为接受生理盐水、U - 50488（5mg/kg）或κ-拮抗剂nor - binaltorphimine（20mg/kg）的组，并评估它们对各种情绪诱发刺激的行为反应。结果表明，接触MPH会降低可卡因位置条件反射和蔗糖偏好，同时增加对焦虑（高架十字迷宫）和应激（强迫游泳）诱发情境的易感性，并且这些行为缺陷会被U - 50488加剧，而通过nor - binaltorphimine治疗可使其恢复正常。这些结果与以下观点一致，即强啡肽/κ-阿片系统失调可能介导发育过程中接触MPH后行为反应的缺陷。此外，这些发现进一步支持了κ-拮抗剂作为治疗焦虑和抑郁相关疾病的潜在药物疗法的观点。
