Psychostimulants and Alpha-1 Adrenoceptor Subtypes

描述(申请人提供)：精神刺激剂诱导的运动变化涉及激活a1-肾上腺素能受体(a1B-AR)的1B亚型。我们知识库中的一个关键空白是可卡因和其他精神刺激剂的行为行为的a1A-AR亚型的功能描述。这个R21应用程序试图利用一种新的仪器/程序来同时评估摄食和运动，以表征大脑α1-AR亚型参与可卡因和安非他明行为的大鼠行为。成年雄性大鼠双侧脑室注射α1A拮抗剂[5-甲基-乌拉地尔]或α1B拮抗剂[L-765,314]5分钟后，分别全身注射盐酸可卡因(0，2.5，5.0，10.0和20.0 mg/kg，ip)或D-苯丙胺硫酸盐(0，0.25，0.5，1.0和2.0 mg/kg，ip)。目的1研究全身可卡因(实验1)或苯丙胺(实验2)对以5-甲基-乌拉地尔或L-765,314为载体的大鼠脑室注射可卡因或苯丙胺后进食和运动的影响。下丘脑室旁核(PVN)内α1受体的激活可引起吞噬功能低下。目的2研究PVNα1-AR亚型在可卡因诱导的摄食和运动改变中的作用(S)。比较双侧PVN内注射载体或5-甲基-乌拉地尔或L-765,314(1或3nmol/只)，然后全身注射可卡因(实验3)或苯丙胺(实验4)的大鼠吞咽功能和运动能力改变的量效曲线。就中脑边缘系统内的多巴胺神经元调节运动并受1-ARs调制而言，目标3的重点是表征伏隔核(NAcc)核心区和壳区(NAcc)内α1-AR亚型对精神刺激剂的低噬和运动作用的不同参与。在实验5和实验6中，在全身注射可卡因或苯丙胺之前，先向三个NAcc区(吻壳、尾壳或核)中的一个区域注射载体或5-甲基-乌拉地尔或L-765,314(1或3nmol/只)。这些研究将促进我们对脑A L-AR亚型行为功能的理解，并可能导致发现不激活大脑强化系统而抑制进食的新药。

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.