González Betina, Raineri Mariana, Cadet Jean Lud, García-Rill Edgar, Urbano Francisco J, Bisagno Veronica
Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Junín 956, Piso 5, C1113 Buenos Aires, Argentina.
Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, Baltimore, MD, United States.
Neuropharmacology. 2014 Dec;87:188-97. doi: 10.1016/j.neuropharm.2014.02.002. Epub 2014 Feb 12.
Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and in animal models. Modafinil is a wake-promoting compound approved for the treatment of sleeping disorders. It is also prescribed off label to treat METH dependence. In the present study, we investigated whether modafinil could improve cognitive deficits induced by sub-chronic METH treatment in mice by measuring visual retention in a Novel Object Recognition (NOR) task. After sub-chronic METH treatment (1 mg/kg, once a day for 7 days), mice performed the NOR task, which consisted of habituation to the object recognition arena (5 min a day, 3 consecutive days), training session (2 equal objects, 10 min, day 4), and a retention session (1 novel object, 5 min, day 5). One hour before the training session, mice were given a single dose of modafinil (30 or 90 mg/kg). METH-treated mice showed impairments in visual memory retention, evidenced by equal preference of familiar and novel objects during the retention session. The lower dose of modafinil (30 mg/kg) had no effect on visual retention scores in METH-treated mice, while the higher dose (90 mg/kg) rescued visual memory retention to control values. We also measured extracellular signal-regulated kinase (ERK) phosphorylation in medial prefrontal cortex (mPFC), hippocampus, and nucleus accumbens (NAc) of METH- and vehicle-treated mice that received modafinil 1 h before exposure to novel objects in the training session, compared to mice placed in the arena without objects. Elevated ERK phosphorylation was found in the mPFC of vehicle-treated mice, but not in METH-treated mice, exposed to objects. The lower dose of modafinil had no effect on ERK phosphorylation in METH-treated mice, while 90 mg/kg modafinil treatment restored the ERK phosphorylation induced by novelty in METH-treated mice to values comparable to controls. We found neither a novelty nor treatment effect on ERK phosphorylation in hippocampus or NAc of vehicle- and METH-treated mice receiving acute 90 mg/kg modafinil treatment. Our results showed a palliative role of modafinil against METH-induced visual cognitive impairments, possibly by normalizing ERK signaling pathways in mPFC. Modafinil may be a valuable pharmacological tool for the treatment of cognitive deficits observed in human METH abusers as well as in other neuropsychiatric conditions. This article is part of the Special Issue entitled 'CNS Stimulants'.
长期使用甲基苯丙胺（METH）会导致人类和动物模型出现持久的认知功能障碍。莫达非尼是一种被批准用于治疗睡眠障碍的促醒化合物。它也被用于非适应症治疗METH成瘾。在本研究中，我们通过在新颖物体识别（NOR）任务中测量视觉记忆保持能力，研究莫达非尼是否能改善亚慢性METH治疗诱导的小鼠认知缺陷。亚慢性METH治疗（1毫克/千克，每天一次，共7天）后，小鼠进行NOR任务，该任务包括对物体识别区域的适应（每天5分钟，连续3天）、训练阶段（2个相同物体，10分钟，第4天）和记忆保持阶段（1个新物体，5分钟，第5天）。在训练阶段前1小时，给小鼠单次注射莫达非尼（30或90毫克/千克）。METH处理的小鼠在视觉记忆保持方面表现受损，在记忆保持阶段对熟悉和新物体表现出同等偏好即可证明。较低剂量的莫达非尼（30毫克/千克）对METH处理的小鼠的视觉记忆保持分数没有影响，而较高剂量（90毫克/千克）可将视觉记忆保持恢复到对照值。我们还测量了在训练阶段接触新物体前1小时接受莫达非尼治疗的METH处理和对照小鼠的内侧前额叶皮质（mPFC）、海马体和伏隔核（NAc）中的细胞外信号调节激酶（ERK）磷酸化水平，并与置于无物体区域的小鼠进行比较。在接触物体的对照处理小鼠的mPFC中发现ERK磷酸化升高，但在METH处理的小鼠中未发现。较低剂量的莫达非尼对METH处理的小鼠的ERK磷酸化没有影响，而90毫克/千克莫达非尼治疗可将METH处理的小鼠中由新事物诱导的ERK磷酸化恢复到与对照相当的值。我们发现，接受急性90毫克/千克莫达非尼治疗的对照和METH处理小鼠的海马体或NAc中，无论是新事物还是治疗对ERK磷酸化均无影响。我们的结果表明莫达非尼对METH诱导的视觉认知障碍具有缓解作用，可能是通过使mPFC中的ERK信号通路正常化实现的。莫达非尼可能是治疗人类METH滥用者以及其他神经精神疾病中观察到的认知缺陷的一种有价值的药理学工具。本文是名为“中枢神经系统兴奋剂”的特刊的一部分。
