The role of receptor desensitization machinery in psychostimulant addiction

描述（由申请人提供）：精神兴奋剂成瘾（PS）是一种强迫性药物寻求的慢性疾病。这种情况被认为是由大脑奖励系统的细胞和分子适应引起的。特别是，在大多数药物滥用的奖励特性中起作用的中边缘多巴胺能系统受到PS的严重影响。长期使用PS增强了伏隔核（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信号级联似乎是PS成瘾的关键。G蛋白偶联受体（包括多巴胺受体）的信号通路受G蛋白偶联受体激酶（GRKs）和阻滞蛋白通过同源脱敏机制调控。我们假设GRKs和抑制蛋白在导致PS成瘾的信号改变中起关键作用。我们最近发现，帕金森啮齿动物和猴子纹状体中GRK6的过表达显著减轻了左旋多巴诱导的运动障碍。由于慢性PS消耗和左旋多巴治疗都会产生间歇性的高多巴胺能状态，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，过表达选定的GRK亚型和/或同时过表达GRK和抑制因子会抑制ps诱导的行为。为了验证这一假设，我们将使用慢病毒在Acb中表达GRKs和GRK/阻滞蛋白组合，并检测对PS的运动致敏性。我们预计阻滞蛋白/GRKs的可用性将增加，以抑制致敏性，并通过慢病毒递送的microRNAs敲低GRK/阻滞蛋白以促进致敏性。目的2旨在阐明在条件位置偏好范式下捕获蛋白/GRK过表达和敲低对PS奖励特性的影响。成瘾治疗的关键是防止复发。我们将确定在Acb中表达的arreins /GRK是否影响可卡因诱导的条件位置偏好的消退和药物诱导的恢复。这些研究将明确抑制因子和GRKs在PS药物成瘾中的作用，并为治疗成瘾提供新的治疗靶点。

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.