Psychostimulants and Alpha-1 Adrenoceptor Subtypes

描述（由申请人提供）：精神兴奋剂引起的运动改变涉及a1 -肾上腺素能受体1B亚型（a1 - ar）的激活。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的行为行为的A- 1A-AR亚型的功能特征。本R21应用程序旨在利用一种新的仪器/程序同时评估进食和运动，表征脑α 1 -AR亚型在大鼠可卡因和安非他明行为行为中的参与。成年雄性大鼠在双侧ICV注射（0、2.5、5.0、10.0和20.0 mg/kg， IP）后5分钟全身注射盐酸可卡因（0、0.25、0.5、1.0和2.0 mg/kg， IP）或硫酸d -安非他明（0、0.25、0.5、1.0和2.0 mg/kg， IP） α 1a拮抗剂[5-甲基-urapadil]或α 1b拮抗剂[L-765,314]。目的1将描述全身可卡因（实验1）或安非他明（实验2）对用5-甲基乌拉帕地尔或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的激活引起吞咽功能减退。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。大鼠在双侧pvn内注射药体或5-甲基乌拉帕地尔或L-765,314（1或3nmol /大鼠），然后全身注射可卡因（实验3），安非他明（实验4），比较吞咽和运动变化的剂量效应曲线。中边缘系统内的多巴胺神经元调节运动，并被。α 1-AR， Aim 3的重点是表征α 1-AR亚型在伏隔核（NAcc）核心和壳区对精神兴奋剂的吞咽和运动作用的不同参与。在实验5和6中，在全身注射可卡因或安非他明之前，在三个NAcc区域（吻侧壳、尾侧壳或核心）中，双侧注射载体或5-甲基-乌拉帕地尔或L-765,314（1或3nmol /大鼠）。这些研究将促进我们对大脑a - ar亚型行为功能的理解，并可能导致发现在不激活大脑强化系统的情况下抑制进食的新药。

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.