Effects of the nicotinic agonist varenicline on the performance of tasks of cognition in aged and middle-aged rhesus and pigtail monkeys.
Effects of the nicotinic agonist varenicline on the performance of tasks of cognition in aged and middle-aged rhesus and pigtail monkeys.
复制标题
烟碱受体激动剂伐尼克兰对中老年恒河猴和猪尾猴认知任务表现的影响。
DOI：
10.1007/s00213-015-4154-0
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发表时间：
2016
影响因子：
3.4
通讯作者：
Callahan,PatrickM
中科院分区：
文献类型：
--
作者：
TerryJr,AlvinV;Plagenhoef,Marc;Callahan,PatrickM
由于药物开发成本的上升，特别是在神经精神病学领域，人们越来越关注为现有批准的药物寻找新的临床用途（即药物再利用）。目的本研究的目的是在动物实验中评估戒烟药物伐尼克兰作为α4β2部分激动剂和α7烟碱受体完全激动剂作为认知障碍治疗药物的潜力。方法对中老年猴子口服剂量为0.01 ~ 0.3 mg/kg的varenicline对延迟匹配样本（DMTS）任务中的工作/短期记忆、DMTS- d的分心性以及氯胺酮损伤的逆转学习任务中的认知灵活性的影响进行了评估。结果在DMTS和DMTS- d任务的剂量效应研究中，伐尼克兰对表现的影响无统计学意义。然而，个体化的“最佳剂量”在单独的场合重复使用时是有效的（即，在长延迟时提高DMTS准确性，在短延迟时提高DMTS- d准确性，分别比基线高出约13.6和19.6个百分点）。在逆向学习研究中，氯胺酮损害了准确性，增加了持续性反应，经评估的三种剂量的伐尼克兰都减弱了这种影响。结论：虽然伐尼克兰对不同行为任务的影响不大，但这些数据表明，伐尼克兰可能有潜力作为一种重新用途的药物，用于治疗与衰老相关的认知障碍（如阿尔茨海默病），以及那些不一定与老年相关的认知障碍（如精神分裂症）。
RationaleDue to the rising costs of drug development especially in the field of neuropsychiatry, there is increasing interest in efforts to identify new clinical uses for existing approved drugs (i.e., drug repurposing).ObjectivesThe purpose of this work was to evaluate in animals the smoking cessation agent, varenicline, a partial agonist at α4β2 and full agonist at α7 nicotinic acetylcholine receptors, for its potential as a repurposed drug for disorders of cognition.MethodsOral doses of varenicline ranging from 0.01 to 0.3 mg/kg were evaluated in aged and middle-aged monkeys for effects on the following: working/short-term memory in a delayed match to sample (DMTS) task, distractibility in a distractor version of the DMTS (DMTS-D), and cognitive flexibility in a ketamine-impaired reversal learning task.ResultsIn dose-effect studies in the DMTS and DMTS-D tasks, varenicline was not associated with statistically significant effects on performance. However, individualized “optimal doses” were effective when repeated on a separate occasion (i.e., improving DMTS accuracy at long delays and DMTS-D accuracy at short delays by approximately 13.6 and 19.6 percentage points above baseline, respectively). In reversal learning studies, ketamine impaired accuracy and increased perseverative responding, effects that were attenuated by all three doses of varenicline that were evaluated.ConclusionsWhile the effects of varenicline across the different behavioral tasks were modest, these data suggest that varenicline may have potential as a repurposed drug for disorders of cognition associated with aging (e.g., Alzheimer’s disease), as well as those not necessarily associated with advanced age (e.g., schizophrenia).