Dopamine Receptor Regulation by GRKs in Drug Abuse

GRKs 在药物滥用中对多巴胺受体的调节

• 批准号: 7049416
• 负责人: Richard T Premont
• 金额: $ 29.38万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049416
• 关键词: G protein coupled receptor kinase; biological signal transduction; cocaine; corpus striatum; dopamine receptor; drug abuse; enzyme activity; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; neuroregulation; nucleus accumbens; receptor coupling

DESCRIPTION (provided by applicant): Drug abuse is a major social problem in the United States, with an estimated 15 million individuals addicted and millions more incarcerated, in addition to many billions of dollars of direct and indirect costs. Abused drugs share two common properties: they provide an initial rewarding "high," and their use sets in motion a chain of neurochemical changes that ultimately lead to continued drug-seeking behavior, often despite diminished satisfaction by the user. Many abused drugs affect the neuromodulator dopamine, which acts through binding and activation of a family of five G protein-coupled receptors. Dopamine receptors are targets for regulation by G protein-coupled receptor kinases (GRKs), which phosphorylate dopamine-bound, activated receptors and reduce the ability of these receptors to activate downstream signaling pathways. We have created mice bearing targeted deletion of the GRK6 gene, and here show that these knockout animals exhibit a profound supersensitivity to the locomotor effects of cocaine. Cocaine acts by inhibiting the presynaptic transporters, which remove released dopamine from synapses, allowing endogenous dopamine to accumulate to high levels and to activate dopamine receptors to a high degree. These GRK6 knockout animals appear to have normal levels of dopamine receptors, but exhibit a markedly increased coupling of these receptors to G proteins. These results suggest the hypothesis that dopamine receptor regulation by GRK6 is an important component of the mechanisms that control dopamine receptor responsiveness to drugs of abuse and that altered GRK6 function may be a predisposing factor favoring drug addiction. We will use studies in genetically-modified mice and in model cells systems to define the importance of GRK6 regulation of dopamine receptors for drug abuse. We will determine whether loss of GRK6 affects responses to other drugs of abuse, and investigate the role of GRK6 in additional behavioral and neurochemical correlates of drug addiction. We will identify the dopamine receptor subtype(s) that GRK6 acts on in mouse striatum, and investigate whether other GRKs have similar effects. Finally, we will use transgenic and conditional knockout approaches in mice to explore whether dopamine receptor regulation by GRK6 is important postsynaptically, presynaptically, or both. The results of these studies will define the role of GRK6 in setting the basal tone of dopamine signaling in the striatum.

描述（由申请人提供）：药物滥用是美国的一个主要社会问题，估计有1500万人上瘾，数百万人被监禁，此外还有数十亿美元的直接和间接成本。滥用药物有两个共同的特性：它们提供了一种最初的“快感”，它们的使用引发了一系列神经化学变化，最终导致持续的药物寻求行为，尽管使用者的满意度往往会降低。许多滥用药物影响神经调节剂多巴胺，它通过结合和激活一个5个G蛋白偶联受体家族来起作用。多巴胺受体是G蛋白偶联受体激酶（GRKs）调控的靶点，其磷酸化多巴胺结合的激活受体，并降低这些受体激活下游信号通路的能力。我们创造了带有GRK6基因靶向缺失的小鼠，并在这里表明，这些敲除动物对可卡因的运动效应表现出深刻的超敏感性。可卡因通过抑制突触前转运蛋白起作用，突触前转运蛋白清除突触释放的多巴胺，使内源性多巴胺积累到高水平，并高度激活多巴胺受体。这些GRK6基因敲除的动物似乎具有正常水平的多巴胺受体，但这些受体与G蛋白的偶联明显增加。这些结果表明，GRK6对多巴胺受体的调节是控制多巴胺受体对药物滥用反应机制的重要组成部分，GRK6功能的改变可能是促进药物成瘾的易感因素。我们将在转基因小鼠和模型细胞系统中进行研究，以确定GRK6调节多巴胺受体对药物滥用的重要性。我们将确定GRK6的缺失是否会影响对其他药物滥用的反应，并研究GRK6在药物成瘾的其他行为和神经化学相关中的作用。我们将确定GRK6在小鼠纹状体中作用的多巴胺受体亚型，并研究其他grk是否具有类似的作用。最后，我们将在小鼠中使用转基因和条件敲除方法来探索GRK6对多巴胺受体的调节是否在突触后、突触前或两者都重要。这些研究的结果将确定GRK6在纹状体多巴胺信号的基础音调设置中的作用。