ADENOSINE A2 RECEPTORS AND PSYCHOSTIMULANT INTERACTIONS

腺苷 A2 受体和精神兴奋剂的相互作用

• 批准号: 3214168
• 负责人: STEVEN A REEVES
• 金额: $ 22.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3214168
• 关键词: adenosine; amphetamines; biomarker; cell type; cocaine; corpus striatum; dopamine receptor; drug addiction antagonist; drug interactions; dyes; gene expression; immunocytochemistry; in situ hybridization; inhibitor /antagonist; laboratory rat; limbic system; messenger RNA; neurochemistry; neurotransmitter receptor; northern blottings; nucleic acid probes; protein sequence; psychotropic drugs; radiotracer; reinforcer

Pharmacological manipulations which attenuate the behavioral effects of amphetamine (AMPH) and cocaine (COC) have potential to be important agents for modifying the abuse potential of psychostimulants. The behavioral effects of AMPH are dependent on activation of dopamine (DA) receptors in the striatum and limbic forebrain, and are modulated by the A2 subtype of adenosine receptor. A2 receptors are expressed abundantly and exclusively in forebrain areas enriched in DA receptors. We have recently isolated the rat A2 adenosine receptor cDNA. We are now able to test the hypothesis that modulation of the behavioral effects of AMPH by A2 receptors results from co-activation of A2 and DA receptors residing on a subset of forebrain neurons and subsequent modulation of post-receptor cellular responses in those neurons. Similar cellular mechanisms may underlie the modulatory effects of adenosinergic agents on the behavioral effects of COC. The goals of this grant are to identify the anatomical systems in striatum and limbic forebrain in which A2 and AI adenosine receptors overlap with DA receptors and to determine if modulation of immediate early genes may be a marker of a subset of forebrain neurons in which a functional interaction between adenosine receptors and AMPH occurs. These experiments will begin to identify nuclear mechanisms which underlie the interactions of A2 receptors and psychostimulants. Three aims are proposed: (1) Determine the localization of A2 receptor mRNA with neurons expressing DA receptor genes and with other neurochemical markers within the striatum and limbic forebrain, (2) Identify the cell types in the striatum and limbic forebrain which express the AI adenosine receptor gene, and (3) Determine whether forebrain A2 adenosine receptors are linked to the same immediate early genes as AMPH. Study of the forebrain A2 adenosine receptor may lead to the identification of anatomical circuits and cellular mechanisms, and novel strategies for their independent regulation, which modulate the rewarding properties of psychostimulants and, more generally, activity of the dopaminergic system in brain.

药物操作，减轻行为的影响， 安非他明（AMPH）和可卡因（COC）具有重要的潜力 用于改变精神兴奋剂的滥用可能性的药剂。 的 AMPH的行为效应依赖于多巴胺（DA）的激活 受体在纹状体和边缘前脑，并调制的 腺苷受体A2亚型。 A2受体大量表达 并且只存在于富含DA受体的前脑区域。 我们有 最近分离出大鼠A2腺苷受体cDNA。 我们现在能够 验证AMPH的行为效应的调节通过以下方式来实现的假设： A2受体由A2和DA受体的共激活引起， 对前脑神经元的一个子集和随后的调制 这些神经元中的受体后细胞反应。 类似的细胞 可能是腺苷能药物调节 COC的行为效应 该补助金的目标是确定 纹状体和边缘前脑的解剖系统，其中A2和 AI腺苷受体与DA受体重叠，并确定是否 立即早期基因的调节可能是一个亚群的标记， 在前脑神经元中，腺苷 受体和AMPH发生。 这些实验将开始识别 A2受体相互作用的核机制， 精神兴奋剂 提出了三个目标：（1）确定 A2受体mRNA在表达DA受体的神经元中的定位 基因以及纹状体和边缘系统内的其他神经化学标记 前脑，（2）识别纹状体和边缘系统的细胞类型 表达AI腺苷受体基因的前脑，和（3）确定 前脑A2腺苷受体是否与同样的直接 早期基因如AMPH。 前脑A2腺苷受体的研究可能 导致解剖电路和细胞的识别 机制和新的战略，为他们的独立监管， 调节精神兴奋剂的奖励特性， 一般来说，大脑中多巴胺能系统的活动。