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

• 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
• 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

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）：对精神刺激剂（PS）的成瘾是强迫性药物的慢性疾病。人们认为这种情况是由脑奖励系统中的细胞和分子适应引起的。尤其是，中断的多巴胺能系统在奖励大多数滥用药物的特性中发挥作用，受到PS的严重影响。慢性PS的使用增强了伏隔核（ACB）中D1多巴胺受体介导的信号传导，并且过度活跃的D1受体cAMP-PKA信号级联对于PS成瘾似乎至关重要。 G蛋白偶联受体的信号传导，包括多巴胺受体，受G蛋白偶联受体激酶（GRKS）的调节，并通过同源脱敏机制来调节。我们假设GRK和逮捕蛋白在信号改变PS的信号变化中起着关键作用。我们最近确定，帕金森氏啮齿动物和猴子纹状体中GRK6的过表达显着缓解了L-DOPA引起的运动障碍。由于慢性PS的消耗和L-DOPA处理都会产生间歇性高巴伯能状态，因此在这两种情况下，许多分子适应性均常见。因此，该证据表明，精选的GRK同工型和/或同时对GRK的过表达和/或逮捕蛋白会抑制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ACB中的GRK和GRK/逮捕蛋白组合，并检查对PS的运动敏化。我们预计，逮捕蛋白/GRK的可用性会增加，以抑制通过慢病毒的microRNA抑制敏化和GRK/逮捕蛋白敲低以促进它。 AIM 2旨在阐明逮捕蛋白/GRK过表达的影响以及敲低对条件位置偏好范式中测得的PS的奖励性能的影响。成瘾治疗的关键点是预防复发。我们将确定在ACB中表达的逮捕蛋白/GRK是否会影响可卡因诱导的条件地位偏好的灭绝和药物诱导的恢复。这些研究将定义逮捕蛋白和GRK在对PS药物上瘾中的作用，并提出新的治疗靶标的来治疗成瘾。 公共卫生的相关性：对精神刺激药物（例如可卡因）的人非常渴望药物，每天都必须踩踏以保持无毒。目前，我们仍然很糟糕地理解该药物成瘾是如何形成的，并且没有方法可以治疗对精神刺激剂的成瘾。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吸毒成瘾中是否重要，以及我们是否可以针对它们来帮助人们打击成瘾并防止恢复毒品的行为。