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种新颖而引人注目的目标。它在大脑中的表达在很大程度上仅限于伏隔核和纹状体，在那里多巴胺，谷氨酸和其他神经递质有助于精神刺激剂的敏感和增强作用。 纹状体A2A受体可以调节这些神经递质的释放及其突触后作用。 此外，它影响了精神刺激物的急性行为影响，并且（基于我们的初步研究）由反复的精神刺激暴露引起的行为敏化。 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不足。我们提出（响应NIDA PA-99-033），以研究A2A受体在行为敏化和精神刺激成瘾的自我管理模型中的作用。我们的核心假设是，A2A受体失活减弱了由反复的精神刺激施用引起的行为和生化变化，将使用A2A受体灭活的互补遗传和经典药理方法系统地测试。 具体的目标1将表征苯丙胺诱导的运动敏化和可卡因自我给药的衰减。 然后，A2a受体拮抗剂对精神刺激剂诱导的敏化的发展和表达的影响将与A2A KO表型相关。 具体的目标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理。体内微透析研究将重点介绍A2A受体失活如何影响多巴胺，谷氨酸和乙酰胆碱的增强，从而有助于行为敏感。 具体目标2b试图鉴定行为敏化的A2A受体调节涉及的突触后机制。 我们将研究A2A受体缺乏症对持续行为敏化的突触后适应性的潜在介体（DeltafosB）和调节剂（NAC-1）的影响。这些研究将共同​​阐明A2A受体在心理刺激剂引起的成瘾行为中的作用，因此可以鼓励发展新颖的，特定的特定策略来治疗心理刺激性虐待和相关的成瘾障碍