The role of receptor desensitization machinery in psychostimulant addiction

描述（由申请人提供）：精神兴奋剂（PS）成瘾是一种慢性强迫性药物寻求。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，其中发挥了作用，在奖励性质的大多数药物滥用，是严重影响PS。PS的长期使用增强了多巴胺D1受体介导的中脑核（Acb）信号转导，过度活跃的D1受体-cAMP-PKA信号级联反应可能是PS成瘾的关键。G蛋白偶联受体（包括多巴胺受体）的信号转导通过同源脱敏机制由G蛋白偶联受体激酶（GRKs）和抑制蛋白（arrestins）调节。我们假设GRKs和arrestins在PS成瘾的信号改变中起关键作用。我们最近已经确定，GRK6在帕金森病啮齿动物和猴子的纹状体中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L-DOPA治疗均产生间歇性高多巴胺能状态，因此许多分子适应性改变对于这两种情况是共同的。因此，这一证据表明，选择GRK亚型的过表达和/或GRK和抑制蛋白的同时过表达将抑制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GRK和GRK/抑制蛋白组合，并检查对PS的运动致敏性。我们期望增加arrestins/GRKs的可用性来抑制敏化和GRK/arrestin敲低通过慢病毒递送的microRNAs来促进it.Aim 2旨在阐明arrestin/GRK过表达和敲低对条件性位置偏爱范例中测量的PS奖励特性的影响。成瘾治疗的关键点是预防复发。我们将确定Acb中表达的arrestins/GRK是否影响可卡因诱导的条件性位置偏爱的消退和药物诱导的恢复。这些研究将明确arrestins和GRKs在PS药物成瘾中的作用，并提出治疗成瘾的新靶点。 公共卫生相关性：对可卡因等精神兴奋剂上瘾的人对毒品有强烈的渴望，每天都要挣扎着保持无毒。目前，我们对药物成瘾的形成机制还知之甚少，对精神兴奋剂成瘾的治疗也没有明确的方法。该项目旨在探索被称为G蛋白偶联受体激酶和抑制蛋白的蛋白质是否在药物成瘾中很重要，以及我们是否可以靶向它们来帮助人们对抗成瘾并防止寻求药物行为的复发。

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.