Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, Newcastle, UK.
Neuropsychopharmacology. 2011 Dec;36(13):2774-81. doi: 10.1038/npp.2011.224. Epub 2011 Sep 28.
Ketamine, an NMDA-receptor antagonist, produces cognitive deficits in humans in a battery of tasks involving attention and memory. Nicotine can enhance various indices of cognitive performance, including working memory span capacity measured using the odor span task (OST). This study examined the effects of a sub-chronic ketamine treatment to model cognitive deficits associated with schizophrenia, and to evaluate the effectiveness of nicotine, antipsychotic clozapine, and the novel mGlu2/3 agonist, LY404039, in restoring OST performance. Male hooded Lister rats were trained in the OST, a working memory task involving detection of a novel odor from an increasing number of presented odors until they exhibited asymptotic levels of stable performance. Sub-chronic ketamine exposure (10 and 30 mg/kg i.p. for 5 consecutive days) produced a dose-dependent impairment that was stable beyond 14 days following exposure. In one cohort, administration of graded doses of nicotine (0.025-0.1 mg/kg) acutely restored the performance in ketamine-treated animals, while significant improvements in odor span were observed in control subjects. In a second cohort of rats, acute tests with clozapine (1-10 mg/kg) and LY404039 (0.3-10 mg/kg) failed to reverse ketamine-induced deficits in doses that were observed to impair performance in the control groups. These data suggest that sub-chronic ketamine exposure in the OST presents a valuable method to examine novel treatments to restore cognitive impairments associated with neuropsychiatric disorders such as schizophrenia. Moreover, it highlights a central role for neuronal nicotinic receptors as viable targets for intervention that may be useful adjuncts to the currently prescribed anti-psychotics.
氯胺酮，一种 NMDA 受体拮抗剂，在一系列涉及注意力和记忆的任务中，会在人类身上产生认知缺陷。尼古丁可以增强各种认知表现的指标，包括使用气味跨度任务（OST）测量的工作记忆跨度能力。本研究检查了亚慢性氯胺酮治疗对模拟与精神分裂症相关的认知缺陷的影响，并评估了尼古丁、抗精神病药氯氮平（clozapine）和新型 mGlu2/3 激动剂 LY404039 恢复 OST 表现的有效性。雄性 Hooded Lister 大鼠在 OST 中接受训练，这是一项涉及从越来越多呈现的气味中检测到新气味的工作记忆任务，直到它们表现出稳定的渐近水平。亚慢性氯胺酮暴露（连续 5 天腹腔注射 10 和 30mg/kg）产生了剂量依赖性的损伤，暴露后 14 天以上仍保持稳定。在一个队列中，给予不同剂量的尼古丁（0.025-0.1mg/kg）可急性恢复氯胺酮处理动物的表现，而在对照组中观察到气味跨度的显著改善。在第二组大鼠中，氯氮平和 LY404039 的急性试验（1-10mg/kg 和 0.3-10mg/kg）未能在观察到的损害对照组表现的剂量下逆转氯胺酮引起的缺陷。这些数据表明，OST 中的亚慢性氯胺酮暴露提供了一种有价值的方法来研究恢复与神经精神障碍（如精神分裂症）相关的认知障碍的新治疗方法。此外，它强调了神经元烟碱受体作为干预的可行靶点的中心作用，这可能是目前规定的抗精神病药物的有用辅助手段。
