A2A Adenosine Receptors in Psychostimulant Sensitization

A2A 腺苷受体在精神兴奋剂致敏中的作用

• 批准号: 6327426
• 负责人: MICHAEL A SCHWARZSCHILD
• 金额: $ 29.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-25 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6327426
• 关键词: amphetamines; basal ganglia; behavioral habituation /sensitization; central nervous system stimulants; cocaine; corpus striatum; drug addiction; gene expression; gene targeting; genetically modified animals; laboratory mouse; microdialysis; neurochemistry; neurotransmitter transport; nucleus accumbens; psychomotor function; purinergic receptor; substance abuse related behavior; transcription factor

The adenosine A2A receptor offers a novel and compelling target for the modulation of addictive behaviors. Its expression in brain is largely restricted to the nucleus accumbens and straitum, where dopamine, glutamate and other neurotransmitters contribute to the sensitizing and reinforcing effects of psychostimulants. The striatal A2A receptor can modulate the release of these neurotransmitters as well as their postsynaptic effects. In addition, it influences both the acute behavioral effects of psychostimulants, and (based on our preliminary studies) the behavioral sensitization induced by repeated psychostimulant exposure. These discrete anatomical, neuromodulatory and behavioral features point to an underappreciated role of A2A receptors in basal ganglia physiology and addiction biology. We propose (in response to NIDA PA-99-033) to investigate the role of the A2A receptor in behavioral sensitization and self-administration models of psychostimulant addiction. Our core hypothesis that A2A receptor inactivation attenuates the behavioral and biochemical changes induced by repeated psychostimulant administration will be systematically tested using complementary genetic and classic pharmacological approaches to A2A receptor inactivation. Specific Aim 1 will characterize the attenuation of amphetamine-induced locomotor sensitization and cocaine self-administration observed in A2A receptor knockout (A2A KO) mice. The effects of A2A receptor antagonists on the development and expression of psychostimulant-induced sensitization will then be correlated with the A2A KO phenotype. Specific Aim 2a will explore A2A receptor-facilitated neurotransmitter release as potential presynaptic mechanism of behavioral sensitization. In vivo microdialysis studies will focus on how A2A receptor inactivation affects the enhanced release of dopamine, glutamate and acetylcholine that contributes to behavioral sensitization. Specific Aim 2b seeks to identify postsynaptic mechanisms involved in A2A receptor regulation of behavioral sensitization. We will examine the effects of A2A receptor deficiency on a potential mediator (deltaFosB) and modulator (NAC-1) of the postsynaptic adaptations sustaining behavioral sensitization. Together these studies will clarify the role of A2A receptors in psychostimulant-induced addictive behaviors, and thus may encourage the development of novel, specific strategies for treating psychostimulant abuse and related addiction disorders

腺苷 A2A 受体为调节成瘾行为提供了一个新颖且引人注目的靶点。它在大脑中的表达主要限于伏隔核和层状核，其中多巴胺、谷氨酸和其他神经递质有助于精神兴奋剂的敏化和增强作用。 纹状体 A2A 受体可以调节这些神经递质的释放及其突触后效应。 此外，它还影响精神兴奋剂的急性行为效应，以及（根据我们的初步研究）反复接触精神兴奋剂引起的行为敏化。 这些离散的解剖学、神经调节和行为特征表明 A2A 受体在基底神经节生理学和成瘾生物学中的作用未被充分认识。我们建议（响应 NIDA PA-99-033）研究 A2A 受体在精神兴奋剂成瘾的行为敏化和自我给药模型中的作用。我们的核心假设是，A2A 受体失活会减弱重复服用精神兴奋剂引起的行为和生化变化，我们将使用 A2A 受体失活的互补遗传和经典药理学方法进行系统测试。 具体目标 1 将表征在 A2A 受体敲除 (A2A KO) 小鼠中观察到的苯丙胺诱导的运动敏化和可卡因自我给药的减弱。 A2A 受体拮抗剂对精神兴奋剂诱导的致敏的发生和表达的影响将与 A2A KO 表型相关。 具体目标 2a 将探索 A2A 受体促进的神经递质释放作为行为敏化的潜在突触前机制。体内微透析研究将重点关注 A2A 受体失活如何影响多巴胺、谷氨酸和乙酰胆碱的增强释放，从而促进行为敏化。 具体目标 2b 旨在确定参与 A2A 受体行为敏化调节的突触后机制。 我们将研究 A2A 受体缺陷对维持行为敏化的突触后适应的潜在介质 (deltaFosB) 和调节器 (NAC-1) 的影响。这些研究将共同​​阐明 A2A 受体在精神兴奋剂引起的成瘾行为中的作用，从而可能鼓励开发新的、具体的策略来治疗精神兴奋剂滥用和相关的成瘾性疾病