A1/A2A Receptors and Caffeine Psychostimulation

咖啡因是最广泛使用的精神活性物质。据估计，咖啡因 全世界所有来源的消耗量平均约为70 mg/人/天，在美国和加拿大约为220 mg/天/人。适量摄入咖啡因会对人体产生整体的精神刺激作用（减少疲劳，提高表现），而有害副作用的风险很小。已知咖啡因作用于多种分子靶点。因此，根据剂量，咖啡因可以在完整的生物体中产生许多不同的影响。目前，咖啡因被认为主要通过阻断脑腺苷，特别是A1和A2 A受体来发挥其作用。然而，证据是间接的，其他分子靶点的可能作用，特别是在较高剂量的不良反应中，仍有待进一步研究。 测定 拟议研究的总体目标是最终评估AI和A2 A受体以及中枢与外周Aj/AaA受体对成熟和发育中动物中咖啡因的精神兴奋剂和心血管作用的贡献。该提议是建立在我们成功开发两种新型腺苷受体敲除模型的基础上：同源Ai-A2 A受体双敲除和条件性组织特异性A2 A受体敲除小鼠。通过这些新的敲除模型，结合分子、神经化学和药理学分析，我们将验证以下假设：（1）前脑A2 A受体对咖啡因的精神兴奋特性至关重要， AI和A2 A受体介导了成年动物中咖啡因的大部分效应;（2）AI和A2 A受体都有助于对急性咖啡因的心血管反应;（3）咖啡因对未成熟动物的短期和长期效应与成年动物的效应不同，并且由不同的分子靶点介导。 从这些研究中获得的信息将提供腺苷受体亚型在介导咖啡因的精神兴奋作用中的作用的最清晰的评估。这也将揭示围产期咖啡因暴露的长期影响，这可能具有显着的公共卫生相关性。这些知识将大大提高我们对咖啡因的精神兴奋剂作用的理解，并为健康使用咖啡因作为兴奋剂以提高人类表现的指导方针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.