Buccafusco Jerry J
Alzheimer's Research Center, Medical College of Georgia, Augusta, GA 30912-2300, USA.
J Alzheimers Dis. 2008 Dec;15(4):709-20. doi: 10.3233/jad-2008-15414.
Non-human primates have served as subjects for studies of the cognition-enhancing potential of novel pharmacological agents for over 25 years. Only recently has a greater appreciation of the translational applicability of this model been realized. Though most Old-World monkeys do not appear to acquire an Alzheimer's-like syndrome in old age, their value resides in the brain physiology they have in common with humans. Paradigms like the delayed matching-to-sample task engender behavior that models aspects of working memory that are substrates for the actions of cognition-enhancing drugs. Our studies have provided information relevant to factors that limit the effectiveness of clinical trial design for compounds that potentially improve cognition. For example, cognition-enhancing compounds from different pharmacological classes, when administered to monkeys, can exhibit remarkable pharmacodynamic effects that outlast the presence of the drug in the body. Studies with non-human primates also can provide information regarding dose ranges and individual subject sensitivity experienced in the clinic. Components of working memory are differentially sensitive to drug effects and may be characterized by different dose ranges for certain compounds, even within the same task. Examples are provided that underscore the possible idiosyncrasies of drug action in the pharmacology of cognition--which could be of critical importance in the design of clinical trials.
25多年来，非人类灵长类动物一直作为新型药理制剂认知增强潜力研究的对象。直到最近，人们才更加认识到这个模型在转化应用方面的价值。虽然大多数旧世界猴在老年时似乎不会患上类似阿尔茨海默病的综合征，但它们的价值在于其与人类共有的大脑生理学特征。像延迟匹配样本任务这样的范式会产生一些行为，这些行为模拟了工作记忆的某些方面，而工作记忆是认知增强药物作用的基础。我们的研究提供了与限制潜在改善认知的化合物临床试验设计有效性的因素相关的信息。例如，不同药理类别的认知增强化合物给猴子服用时，可能会表现出显著的药效学效应，其持续时间超过药物在体内的存在时间。对非人类灵长类动物的研究还可以提供有关临床中所经历的剂量范围和个体受试者敏感性的信息。工作记忆的各个组成部分对药物作用的敏感性不同，对于某些化合物，即使在同一任务中，也可能具有不同的剂量范围特征。文中给出了一些例子，强调了认知药理学中药物作用可能存在的特异性——这在临床试验设计中可能至关重要。
