Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
J Alzheimers Dis. 2010;20 Suppl 1:S17-24. doi: 10.3233/JAD-2010-1403.
Caffeine is well known for its complex pharmacological actions, in part reflecting the multiple molecular targets of caffeine. The adenosine receptors are the primary extracellular targets of caffeine. Since caffeine has similar affinity for several adenosine receptors, it has been difficult to determine which receptor subtypes mediate caffeine's effects using pharmacological tools. The development of genetic mutant mice deficient in adenosine receptors and other signaling molecules has allowed targeted inquiry into the molecular targets by which caffeine elicits its biological effects on behavior and gene expression. This review summarizes recent work using genetic knockout models to elucidate the mechanisms of caffeine action in the brain. This review focuses on insights into caffeine action from genetic knockout models on: (1) the molecular basis for caffeine's effects on psychomotor activity; (2) the involvement of adenosine receptors in caffeine-mediated arousal and cognitive effects; and (3) a novel approach using knockout animals coupled with microarray profiling to validate multiple molecular targets of caffeine in striatal gene expression.
咖啡因具有复杂的药理学作用，这在一定程度上反映了咖啡因的多种分子靶点。腺苷受体是咖啡因的主要细胞外靶点。由于咖啡因对几种腺苷受体具有相似的亲和力，因此使用药理学工具很难确定哪种受体亚型介导咖啡因的作用。缺乏腺苷受体和其他信号分子的基因敲除突变小鼠的开发，使得通过靶向询问来研究咖啡因对行为和基因表达产生生物学影响的分子靶点成为可能。本综述总结了最近使用基因敲除模型阐明咖啡因在大脑中作用机制的工作。本综述重点介绍了从基因敲除模型中获得的关于咖啡因作用的以下见解：（1）咖啡因对精神运动活动影响的分子基础；（2）腺苷受体在咖啡因介导的觉醒和认知作用中的作用；以及（3）一种使用敲除动物结合微阵列分析来验证纹状体基因表达中咖啡因的多个分子靶点的新方法。
