A1/A2A Receptors and Caffeine Psychostimulation

咖啡因是消费最广泛的精神活性物质。据估计，咖啡因 全球所有来源的平均摄入量约为70毫克/人/天，美国和加拿大为-220毫克/天/人。适量摄入咖啡因对人类产生全面的心理刺激作用(减少疲劳，提高表现)，几乎没有产生有害副作用的风险。众所周知，咖啡因可以作用于多种分子靶点。因此，根据剂量的不同，咖啡因在完整的生物体中可以产生许多不同的效果。目前，咖啡因被认为主要通过阻断脑腺苷发挥作用，特别是AI和A2A受体。然而，证据是间接的，其他分子靶点的可能贡献，特别是在更高剂量的不良影响中，仍有待于 下定决心。 拟议研究的总体目标是最终评估AI和A2A受体以及中枢和外周AJ/AAA受体对咖啡因在成熟和发育中的动物的精神刺激和心血管效应中的作用。这一建议建立在我们成功开发了两种新型腺苷受体基因敲除模型的基础上：同源基因Ai-A2a受体双基因敲除和条件性、组织特异性A2a受体基因敲除小鼠。通过这些新的基因敲除模型，再加上分子、神经化学和药理学分析，我们将检验以下假设：(1)前脑A2a受体对咖啡因和联合阻滞剂的精神刺激特性至关重要 AI型和A2A型受体介导了咖啡因对成年动物的大部分作用；(2)AI型和A2A型受体都参与了急性咖啡因引起的心血管反应；(3)咖啡因对未成熟动物的短期和长期作用不同于成年动物的作用，并且是由不同的分子靶点介导的。 来自这些研究的信息将提供迄今为止对腺苷受体亚型在介导咖啡因的精神刺激效应中的作用的最清晰的评估。这也将阐明围产期接触咖啡因的长期影响，这可能与公共卫生有重大关系。这些知识将大大提高我们对咖啡因的精神刺激作用的理解，并为指导健康使用咖啡因作为兴奋剂以提高人类表现提供神经生物学基础。

Caffeine is the most widely consumed psychoactive substance. It is estimated that caffeine consumption from all sources averages approximately 70 mg/person/day worldwide and -220 mg/day/person in the US and Canada. Moderate consumption of caffeine produces overall psychostimulant effects (reducing fatigue, enhancing performance) in humans with little risk of harmful side effects. Caffeine is known to act at a multitude of molecular targets. Therefore, depending on dose, caffeine can produce many different effects in the intact organism. Presently, caffeine is believed to exert its effects primarily by blocking brain adenosine, particularly AI and A2A receptors. However, the evidence is circumstantial and the possible contribution of other molecular targets, particularly in the untoward effects of higher doses, remains to be determined. The overall goal of the proposed studies is to conclusively assess the contribution of the AI and A2A receptors and of the central versus peripheral Aj/AaA receptors to caffeine's psychostimulant and cardiovascular effects in mature and developing animals. This proposal is built on our successful development of two novel adenosine receptor knockout models: the congenic Ai-A2A receptor double knockout and a conditional, tissue-specific A2A receptor knockout mouse. With these novel knockout models coupled with molecular, neurochemical and pharmacological analyses, we will test the hypotheses that: (1) forebrain A2A receptors are essential for the psychostimulant properties of caffeine, and combined blockade of AI and A2A receptors mediate most effects of caffeine in adult animals; (2) both AI and A2A receptors contribute to the cardiovascular response to acute caffeine, and (3) the short and long-term effects of caffeine on immature animals are distinct from effects in adults and are mediated by different molecular targets. The information derived from these studies will provide the clearest assessment yet of the role of subtypes of adenosine receptors in mediating caffeine's psychostimulant effect. This will also shed light on the long-term effects of perinatal caffeine exposure, which may have significant public health relevance. This knowledge will significantly enhance our understanding of caffeine's psychostimulant action, and provide a neurobiological basis for guidelines for healthy usage of caffeine as a stimulant to improve human performance.