Mechanism of drug addiction

吸毒成瘾的机制

• 批准号: 8018727
• 负责人: Howard H Gu
• 金额: $ 33.41万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018727
• 关键词: Affinity; Animals; Back; Backcrossings; Behavioral; Binding; Biochemical; Brain; Brain region; Cocaine; Cocaine Dependence; Complex; Data; Development; Dopamine; Dose; Drug Addiction; Drug Exposure; Exhibits; Extinction (Psychology); Genetic; Human; Injection of therapeutic agent; Knock-in Mouse; Knock-out; Knockout Mice; Locomotion; Measures; Methods; Methylphenidate; Modeling; Molecular; Molecular Genetics; Mus; Neurological Models; Neuronal Plasticity; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Principal Investigator; Property; Psychological reinforcement; Relapse; Rewards; Role; Self Administration; Self-Administered; Synapses; Testing; Viral Vector; Wild Type Mouse; adeno-associated viral vector; behavior test; behavioral sensitization; cocaine use; dopamine system; dopamine transporter; drug craving; drug reward; effective therapy; extracellular; insight; mutant; noradrenaline transporter; novel; preference; prevent; programs; psychostimulant; public health relevance; research study; response; serotonin transporter; success; tool; uptake

DESCRIPTION (provided by applicant): Currently, there are no pharmacological treatments for cocaine addiction partly because the mechanism of cocaine addiction is not clear. Cocaine has 3 high affinity targets in the brain, dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). Cocaine binds and blocks the uptake functions of these transporters, resulting in prolonged and elevated transmitter levels in the synapses, which are believed to underlie the stimulating and rewarding effects of cocaine. Surprisingly, knockout mice with DAT, NET, or SERT individually disrupted still exhibit cocaine reward, suggesting that no single transporter is explicitly required for cocaine reward and drugs preventing cocaine inhibition of a single transporter may not be effective. However, compensatory changes in the knockout mice may have altered the reward pathway. To avoid the compensatory changes, we have generated a knock-in mouse line carrying a DAT mutant that retains the uptake function but is insensitive to cocaine inhibition (DAT-KI mice). In these mice, normal doses of cocaine no longer block DAT, stimulate locomotion, or produce reward. Our results indicate that DAT blockade is required for cocaine reward in mice with a functional DAT. Most significantly, it suggests drugs that antagonize cocaine inhibition of DAT should be effective in blocking cocaine reward. DAT-KI mice provide a unique novel tool to investigate the mechanism of the complex cocaine effects. We propose to continue our current studies. We will examine cocaine responses by DAT-KI mice in several other behavioral tests to dissect out the contribution of DAT in the complex effects of cocaine. In addition, we will use AAV vector to re-introduce wild type DAT back into selected brain regions of DAT-KI mice to restore cocaine-induced DA elevation in those selected regions only and study what cocaine responses are restored. This unique approach allows us to correlate cocaine actions in specific brain regions to specific cocaine effects. Our preliminary data show that we are now able to inject AAV in confined brain regions and groups of mice with varying AAV injections restored cocaine responses in either conditioned place preference test only, locomotor stimulation only, both tests, or none of the tests, demonstrating the feasibility of our approach. The success of the proposed project will significantly enhance our understanding on how cocaine produces its complex effects, which are crucial for our efforts in the development of effective treatment for cocaine addiction. PUBLIC HEALTH RELEVANCE: In the proposed study, we will use molecular, genetic, biochemical and behavioral analysis tools to understand the molecular mechanisms of drug addiction. The success of the proposed project will significantly enhance our understanding on how cocaine produces its complex effects, which are crucial for our efforts in the development of effective treatment for cocaine addiction.

描述（由申请人提供）：目前，没有可卡因成瘾的药理学治疗，部分原因是可卡因成瘾的机制尚不清楚。可卡因在大脑，多巴胺转运蛋白（DAT），5-羟色胺转运蛋白（SERT）和去甲肾上腺素转运蛋白（NET）中具有3个高亲和力。可卡因结合并阻止了这些转运蛋白的摄取功能，从而导致突触中的发射机水平延长和升高，这被认为是可卡因的刺激和有益作用的基础。令人惊讶的是，具有DAT，NET或SERT单独破坏的敲除小鼠仍然具有可卡因奖励，这表明没有明确需要可卡因奖励和防止可卡因抑制单个转运蛋白的药物的单一转运蛋白可能是无效的。但是，淘汰小鼠的补偿性变化可能改变了奖励途径。为了避免补偿性变化，我们生成了一条载有鼠标线，该型鼠标载有一个保留摄取功能但对可卡因抑制不敏感的DAT突变体（DAT-KI小鼠）。在这些小鼠中，正常剂量可卡因不再阻止DAT，刺激运动或产生奖励。我们的结果表明，具有功能性DAT的小鼠可卡因奖励需要DAT封锁。最重要的是，它表明药物对可卡因的抑制作用应有效阻止可卡因奖励。 Dat-Ki小鼠提供了一种独特的新颖工具来研究复杂可卡因效应的机理。我们建议继续我们目前的研究。我们将在其他几种行为测试中研究Dat-Ki小鼠的可卡因反应，以剖析DAT在可卡因的复杂作用中的贡献。此外，我们将使用AAV矢量将野生型DAT重新引入DAT-KI小鼠的选定大脑区域，以恢复可卡因诱导的DA升高，仅在这些选定的区域中，研究可卡因反应的恢复。这种独特的方法使我们能够将特定大脑区域的可卡因作用与特定可卡因作用相关联。我们的初步数据表明，我们现在能够在狭窄的大脑区域和一组小鼠中注入AAV，并在任何条件的位置偏好测试中恢复了可卡因的反应，仅在任何条件的位置偏好测试中，仅运动刺激，两种测试，或没有测试，都证明了我们方法的可行性。拟议项目的成功将显着增强我们对可卡因如何产生其复杂作用的理解，这对于我们在开发有效治疗可卡因成瘾方面至关重要。公共卫生相关性：在拟议的研究中，我们将使用分子，遗传，生化和行为分析工具来了解药物成瘾的分子机制。拟议项目的成功将显着增强我们对可卡因如何产生其复杂作用的理解，这对于我们在开发有效治疗可卡因成瘾方面至关重要。