The role of receptor desensitization machinery in psychostimulant addiction

受体脱敏机制在精神兴奋剂成瘾中的作用

基本信息

批准号：
8252147
负责人：
Eugenia V Gurevich
金额：
$ 19.5万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-15 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8252147
关键词：
Addictive Behavior Affect Affinity Agonist Amphetamines Area Arrestins Attenuated Behavior Behavioral Behavioral Paradigm Binding Brain Charge Chronic Cocaine Consumption Corpus striatum structure Cyclic AMP Cyclic AMP-Dependent Protein Kinases Disease Dopamine Dopamine D1 Receptor Dopamine Receptor Dopaminergic Agents Down-Regulation Drug Addiction Extinction (Psychology)G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein-Coupled Receptors GRK6 gene GTP-Binding Proteins Gene Transfer Genes Individual Intake L-DOPA induced dyskinesia Learning Measures Mediating Memory Methods MicroRNAs Modeling Molecular Monkeys Mus Nucleus Accumbens Parkinson Disease Parkinsonian Disorders Pathway interactions Pharmaceutical Preparations Plastics Play Process Property Protein Isoforms Proteins Psychostimulant dependence Rewards Rodent Role Signal Transduction Stress Subfamily lentivirinae System Testing Time Uncertainty Up-Regulation addiction arrestin3 base combat desensitization design disorder later incidence prevention dopamine transporter drug craving drug of abuse drug relapse drug seeking behavior in vivo innovation meetings new therapeutic target novel overexpression preference pressure prevent psychostimulant public health relevance receptor receptor-mediated signaling research study response

项目摘要

DESCRIPTION (provided by applicant): Addiction to psychostimulants (PS) is a chronic condition of compulsive drug seeking. This condition is thought to arise from cellular and molecular adaptations in the brain reward systems. In particular, the mesolimbic dopaminergic system, which plays a role in rewarding properties of most drugs of abuse, is severely affected by PS. The chronic PS use enhances the D1 dopamine receptor-mediated signaling in the nucleus accumbens (Acb), and overactive D1 receptor-cAMP-PKA signaling cascade seems to be critical for PS addiction. The signaling of G protein-coupled receptors, including dopamine receptors, is regulated by G protein-coupled receptor kinases (GRKs) and arrestins via the homologous desensitization mechanism. We hypothesize that GRKs and arrestins play the key role in signaling alterations responsible for addiction to PS. We have recently established that overexpression of GRK6 in the striatum of parkinsonian rodents and monkeys significantly alleviated L-DOPA-induced dyskinesia. Since both chronic PS consumption and L-DOPA treatment produce intermittent hyperdopaminergic states, many molecular adaptations are common for both conditions. Thus, this evidence suggests that overexpression of select GRK isoforms and/or simultaneous overexpression of a GRK and an arrestin would suppress PS-induced behaviors. To test this hypothesis, we will express GRKs and GRK/arrestin combinations in Acb using lentiviruses and examine locomotor sensitization to PS. We expect increased availability of arrestins/GRKs to suppress sensitization and GRK/arrestin knockdown via lentivirally- delivered microRNAs to facilitate it. Aim 2 is designed to elucidate the effect of arrestin/GRK overexpression and knockdown on rewarding properties of PS measured in the conditioned place preference paradigm. The critical point in addiction treatment is prevention of relapse. We will determine whether arrestins/GRK expressed in Acb affects extinction and drug-induced reinstatement of cocaine-induced conditioned place preference. These studies will define the role of arrestins and GRKs in addiction to PS drugs and suggest novel therapeutic targets to treat addiction. PUBLIC HEALTH RELEVANCE: Individuals addicted to psychostimulant drugs, such as cocaine, have strong craving for drugs and have to straggle every day to remain drug-free. At present, we still understand poorly how the drug addiction is formed, and there are no methods to treat addiction to psychostimulants. This project is designed to explore whether the proteins called G protein-coupled receptor kinases and arrestin are important in drug addiction, and whether we could target them to help people combat addiction and prevent reinstatement of drug-seeking behavior.

描述（由申请人提供）：精神兴奋剂成瘾（PS）是一种强迫性寻求药物的慢性病症。这种情况被认为是由大脑奖励系统中的细胞和分子适应引起的。特别是，中脑边缘多巴胺能系统在大多数滥用药物的奖励特性中发挥作用，受到 PS 的严重影响。长期使用 PS 会增强伏隔核 (Acb) 中 D1 多巴胺受体介导的信号传导，而过度活跃的 D1 受体-cAMP-PKA 信号级联似乎对 PS 成瘾至关重要。 G 蛋白偶联受体（包括多巴胺受体）的信号传导由 G 蛋白偶联受体激酶 (GRK) 和视紫红质抑制蛋白通过同源脱敏机制调节。我们假设 GRK 和抑制蛋白在导致 PS 成瘾的信号改变中发挥关键作用。我们最近发现，帕金森病啮齿动物和猴子纹状体中 GRK6 的过度表达可显着缓解左旋多巴引起的运动障碍。由于慢性 PS 消耗和 L-DOPA 治疗都会产生间歇性多巴胺能亢进状态，因此许多分子适应对于这两种情况都是常见的。因此，这一证据表明，选择性 GRK 同工型的过度表达和/或 GRK 和抑制蛋白的同时过度表达将抑制 PS 诱导的行为。为了检验这一假设，我们将使用慢病毒在 Acb 中表达 GRK 和 GRK/arrestin 组合，并检查对 PS 的运动敏感性。我们预计抑制蛋白/GRK 的可用性会增加，以抑制致敏，并通过慢病毒递送的 microRNA 来促进 GRK/抑制蛋白敲低，以促进致敏。目标 2 旨在阐明视紫红质抑制蛋白/GRK 过表达和敲低对在条件位置偏好范式中测量的 PS 奖励特性的影响。成瘾治疗的关键是预防复吸。我们将确定 Acb 中表达的抑制蛋白/GRK 是否影响可卡因诱导的条件性位置偏好的消退和药物诱导的恢复。这些研究将明确视紫红质抑制蛋白和 GRK 在 PS 药物成瘾中的作用，并提出治疗成瘾的新治疗靶点。公共卫生相关性：对可卡因等精神兴奋药物上瘾的人对毒品有强烈的渴望，每天都必须努力保持不吸毒的状态。目前，我们对毒瘾是如何形成的还知之甚少，也没有治疗精神兴奋剂成瘾的方法。该项目旨在探索称为 G 蛋白偶联受体激酶和抑制蛋白的蛋白质在药物成瘾中是否重要，以及我们是否可以针对它们来帮助人们对抗成瘾并防止恢复吸毒行为。