Decamp E, Schneider J S
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, 521 JAH, Philadelphia, PA 19107, USA.
Eur J Neurosci. 2006 Oct;24(7):2098-104. doi: 10.1111/j.1460-9568.2006.05077.x.
Chronic administration of low doses of the neurotoxin MPTP to nonhuman primates induces cognitive deficits similar to those seen in early Parkinson's disease (PD) patients, without the confounding effect of significant motor impairment. The present study assessed the extent to which specific attentional and central executive deficits in chronic low dose (CLD) MPTP-treated monkeys could be modified by nicotinic therapies. Four adult male rhesus monkeys were trained to perform attention and executive function tasks and were then administered low doses of MPTP (dose range: 0.025-0.1 mg/kg, i.v.) over 98-158 days until stable cognitive deficits appeared. Results showed that both nicotine and the alpha4beta4 subtype-selective nAChR agonist SIB-1553A could improve certain aspects of attentional and central executive functioning in this model of early Parkinsonism. Nicotine failed to improve performance of CLD-MPTP-treated animals on an attention set-shifting task while SIB-1553A significantly improved at least some aspects of performance, suggesting that the compound increased the animals' ability to maintain a previously formed response set and restored cognitive flexibility. Both nicotine and SIB-1553A caused a dose-dependent enhancement of performance on the focused attention (cued reaction time) task, decreasing reaction times on both cued and noncued trials. Nicotine caused a significant reduction in reaction times but did not alter the error profile on an impulse (motor readiness) task. SIB-1553A reduced reaction times but caused an increase in bar release (i.e. impulsivity) errors. These data suggest that nicotinic drugs may have therapeutic potential for treating cognitive dysfunction in PD.
对非人类灵长类动物长期给予低剂量神经毒素MPTP会诱发类似于早期帕金森病（PD）患者出现的认知缺陷，而不会产生明显运动障碍这种混淆效应。本研究评估了烟碱疗法对长期低剂量（CLD）MPTP处理的猴子中特定注意力和中枢执行功能缺陷的改善程度。对四只成年雄性恒河猴进行训练，使其执行注意力和执行功能任务，然后在98 - 158天内给予低剂量MPTP（剂量范围：0.025 - 0.1 mg/kg，静脉注射），直至出现稳定的认知缺陷。结果表明，在这个早期帕金森病模型中，尼古丁和α4β4亚型选择性烟碱型乙酰胆碱受体（nAChR）激动剂SIB - 1553A均可改善注意力和中枢执行功能的某些方面。尼古丁未能改善CLD - MPTP处理动物在注意力转换任务中的表现，而SIB - 1553A显著改善了至少部分表现，这表明该化合物提高了动物维持先前形成的反应定势并恢复认知灵活性的能力。尼古丁和SIB - 1553A均使聚焦注意力（线索反应时间）任务的表现呈剂量依赖性增强，减少了线索和非线索试验中的反应时间。尼古丁使反应时间显著缩短，但未改变冲动（运动准备）任务中的错误情况。SIB - 1553A缩短了反应时间，但导致横杆释放（即冲动性）错误增加。这些数据表明，烟碱类药物可能具有治疗帕金森病认知功能障碍的潜力。
