ADENOSINE A2 RECEPTORS AND PSYCHOSTIMULANT INTERACTIONS

减弱阿片受体激动剂的行为效应的药物操作 安非他明(安非他明)和可卡因(COC)可能是重要的 用于改变精神刺激剂滥用潜力的药物。这个 AMPH的行为效应依赖于多巴胺(DA)的激活。 纹状体和边缘前脑中的受体，并受 腺苷受体A2亚型。A2受体大量表达 并且仅存在于富含DA受体的前脑区域。我们有 最近克隆了大鼠A2腺苷受体基因。我们现在能够 测试通过调节AMPH的行为效应的假设 A2受体是A2和DA受体共同激活的结果 关于前脑神经元的一个子集及其随后的调制 这些神经元中的受体后细胞反应。相似的蜂窝 腺苷能药物对血管紧张素转换酶的调节作用机制 COC的行为效应。这笔赠款的目标是确定 纹状体和边缘前脑内A2和A2的解剖系统 AI腺苷受体与DA受体重叠，并确定是否 即刻早期基因的调制可能是一种标记 前脑神经元中腺苷之间的功能性相互作用 受体和安非他明的产生。这些实验将开始识别 A2受体和A2R相互作用的核机制 精神刺激剂。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 基因与纹状体和边缘的其他神经化学标记物 前脑，(2)识别纹状体和边缘的细胞类型 表达AI腺苷受体基因的前脑，以及(3)确定 前脑A2腺苷受体是否与相同的即刻 早期基因如amph。前脑A2腺苷受体的研究可能 导致解剖回路和细胞的识别 机制，以及独立监管的新战略，其中 调节精神刺激剂的奖励特性，以及更多 一般来说，脑内多巴胺能系统的活动。

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.