The role of receptor desensitization machinery in psychostimulant addiction

描述(申请人提供)：精神刺激剂(PS)成瘾是强迫性药物寻求的一种慢性疾病。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，在大多数滥用药物的奖励特性中发挥作用的中脑边缘多巴胺能系统，受到PS的严重影响。慢性PS的使用增强了伏隔核多巴胺D_1受体介导的信号转导，而过度激活的D_1受体-cAMP-PKA信号通路似乎在PS成瘾中起关键作用。G蛋白偶联受体，包括多巴胺受体，通过同源脱敏机制，受G蛋白偶联受体激酶(GRKs)和抑制素的调节。我们推测GRK和拦阻蛋白在PS成瘾的信号转导过程中起关键作用。我们最近证实，在帕金森病啮齿动物和猴子的纹状体中过表达GRK6可以显著缓解L多巴诱导的运动障碍。由于慢性PS消耗和L多巴治疗都会产生间歇性高多巴胺能状态，因此在这两种情况下，许多分子适应都是常见的。因此，这一证据表明，过表达特定的GRK亚型和/或同时过表达GRK和arrestin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/arrestin组合，并检测对PS的运动敏感性。我们期待通过慢病毒传递的microRNA来抑制致敏和抑制GRK/arrestin基因敲除，从而增加拦阻蛋白/GRKs的可用性。目的2旨在阐明Arrestin/GRK过表达和敲除对条件性位置偏爱范式中PS奖赏特性的影响。戒毒的关键是防止复发。我们将确定在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。这些研究将确定阻滞素和GRK在PS药物成瘾中的作用，并提出治疗成瘾的新治疗靶点。 与公共健康相关：对可卡因等精神刺激药物上瘾的人对毒品有强烈的渴望，必须每天挣扎才能保持戒毒。目前，我们对药物成瘾的形成机制还知之甚少，也没有治疗精神刺激剂成瘾的方法。该项目旨在探索被称为G蛋白偶联受体激酶和arrestin的蛋白质是否在药物成瘾中起重要作用，以及我们是否可以针对它们来帮助人们与毒瘾作斗争，防止重新出现寻求毒品的行为。

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.