Psychostimulants and Alpha-1 Adrenoceptor Subtypes

描述（由申请人提供）：精神兴奋剂诱导的运动变化涉及α 1 -肾上腺素受体（α 1B-AR）的1B亚型激活。我们知识库中的一个关键空白是可卡因和其他精神兴奋剂行为作用的1A-AR亚型的功能表征。该R21申请旨在使用一种新的装置/程序同时评估进食和运动，表征大鼠中可卡因和苯丙胺行为作用中大脑α 1-AR亚型的参与。成年雄性大鼠将接受盐酸可卡因的全身注射（0、2.5、5.0、10.0和20.0 mg/kg，IP）或硫酸D-苯丙胺（0、0.25、0.5、1.0和2.0 mg/kg，IP）双侧ICV注射后5分钟（0、3或30 nMol/大鼠）α 1A拮抗剂[5-甲基-乌拉地尔]或α 1B拮抗剂[L-765，314]。目的1将表征全身性可卡因（实验1）或安非他明（实验2）对用溶剂、5-甲基-乌拉地尔或L-765，314预处理（ICV）的大鼠进食和运动的影响。下丘脑室旁核（PVN）内α 1-AR的激活引起食欲减退。目的2将描述PVN α 1-AR亚型在可卡因诱导的摄食和运动变化中的作用。将在接受双侧PVN内输注溶剂或5-甲基-乌拉地尔或L-765，314（1或3 nMol/大鼠），然后全身给予可卡因（实验3）或安非他明（实验4）的大鼠中比较摄食量减少和运动变化的剂量效应曲线。由于中脑边缘系统内的多巴胺神经元调节运动并被.1-AR调制，目标3的重点是表征神经核（NAcc）的核心和外壳区域内的α 1-AR亚型对精神兴奋剂的摄食和运动作用的差异参与。在实验5和6中，在全身注射可卡因或安非他明之前，将向三个NAcc区域（吻壳、尾壳或核）之一中双侧注射溶媒或5-甲基-乌拉地尔或L-765，314（1或3 nMol/大鼠）。这些研究将推进我们对脑α 1-AR亚型的行为功能的理解，并可能导致识别抑制进食而不激活脑强化系统的新药。

DESCRIPTION (provided by applicant): Psychostimulant-induced changes in locomotion involve activation of the 1B subtype of the a 1 -adrenoceptor (a 1B-AR). A key gap in our knowledge base is the functional characterization of the a 1A-AR subtype for the behavioral actions of cocaine and other psychostimulants. This R21 application seeks to characterize the involvement of brain alpha1 -AR subtypes in the behavioral actions of cocaine and amphetamine in rats using a novel apparatus/procedure to concurrently assess feeding and locomotion. Adult male rats will receive systemic injections of cocaine hydrochloride (0, 2.5, 5.0,10.0, and 20.0 mg/kg, IP) or D-amphetamine sulfate (0, 0.25, 0.5,1.0, and 2.0 mg/kg, IP) five minutes after bilateral ICV injections (0, 3 or 30 nMol/rat) of either an alpha1A antagonist [5-methyl-urapadil] or an alpha1B antagonist [L-765,314]. Aim 1 will characterize the effects of systemic cocaine (Exp 1) or amphetamine (Exp 2) on eating and locomotion in rats pretreated (ICV) with either vehicle, 5-methyl-urapadil or L-765,314. Activation of alpha1-ARs within the hypothalamic paraventricular nucleus (PVN) evokes hypophagia. Aim 2 will characterize the role(s) of PVN alpha1-AR subtypes in cocaine-induced changes in feeding and locomotion. Dose-effect curves for changes in hypophagia and locomotion will be compared in rats receiving bilateral intra-PVN infusions of vehicle or 5-methyl-urapadil or L-765,314 (1 or 3 nMol/rat) followed by systemic doses of either cocaine (Exp 3), amphetamine (Exp 4). Insofar as dopamine neurons within the mesolimbic system modulate locomotion and are modulated by .1-ARs, the focus of Aim 3 is to characterize the differential involvement of alpha1 -AR subtypes within the core and shell regions of the nucleus accumbens (NAcc) for the hypophagic and locomotor actions of psychostimulants. In Experiments 5 and 6, systemic injections of cocaine or amphetamine will be preceded by bilateral injections of vehicle or of 5-methyl-urapadil or L-765,314 (1 or 3 nMol/rat) into one of three NAcc regions (rostral shell, caudal shell or core). These studies will advance our understanding of the behavioral functions of brain a l-AR subtypes and may lead to the identification of new drugs that inhibit eating without activating brain reinforcement systems.