Cocaine and monoamine transporters

可卡因和单胺转运蛋白

基本信息

批准号：
7664307
负责人：
Howard H Gu
金额：
$ 32.07万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7664307
关键词：
Affinity Brain Brain region Cocaine Cocaine Abuse Cocaine Dependence Complex Development Disease Dopamine Dose Drug Delivery Systems Ensure Euphoria Excision Exons Future Gene Expression Goals Homeostasis Individual Knock-in Mouse Knockout Mice Knowledge Lead Locomotion Mediating Mental disorders Mus Mutagenesis Mutant Strains Mice Mutate Neomycin Norepinephrine Pathway interactions Pharmaceutical Preparations Pharmacological Treatment Process Property Regulation Rewards Role Second Messenger Systems Self Administration Serotonin Site Slice Surface System Testing Wild Type Mouse addiction behavior test craving dopamine transporter drug candidate drug of abuse dysphoria effective therapy extracellular homologous recombination mRNA Expression monoamine mutant noradrenaline transporter norepinephrine system preference prevent response second messenger serotonin transporter uptake

项目摘要

DESCRIPTION (provided by applicant): Cocaine abuse and addiction continue to be a serious problem in the world. Currently, there is no effective pharmacological treatment for this mental disorder. Our long term goal is to understand the mechanism of cocaine addiction in order to develop effective treatments for this disorder. Cocaine has three known high affinity targets, the dopamine (DA) transporter (DAT), the serotonin (5HT) transporter (SERT), and the norepinephrine (NE) transporter (NET). When cocaine enters the brain it blocks all three transporters and thus increases extracellular DA, 5HT, and NE in various brain regions, resulting in complex cocaine effects. One way to study the role of each transporter is to generate knockout mice with individual transporters deleted. The potential problem with this approach is that adaptive changes to compensate for the complete removal of the critical transporter may alter the reward pathway significantly. We are employing an alternative approach. We are generating knock-in mouse lines carrying a transporter mutant that is insensitive to cocaine inhibition while maintaining functional monoamine uptake. We have generated a knock-in mouse line carrying a cocaine-insensitive DAT mutant that retains substantial uptake activity. In these mice, cocaine no longer produces reward, suggesting that DAT blockade is necessary for cocaine reward. However, DAT mutant mice do not provide information about the roles of NET and SERT in cocaine effects. The specific aims of the proposed study is (1) to construct mutants of SERT and NET that are functional but insensitive to cocaine inhibition; (2) to generate 2 mouse lines with their SERT or NET replaced by the cocaine-insensitive transporter mutants; and (3) to analyze the cocaine responses by the knock-in mice. This study will tell us whether NET or SERT blockade is also necessary for cocaine reward, or it enhances or dampens cocaine reward. Precise knowledge on how DA, 5HT, and NE systems modulate cocaine reward and aversion may suggest potential drug targets to modulate the intensity and dynamics of cocaine reward and aversion. Compounds that dampen the cocaine-induced euphoria and prolong cocaine dysphoria may discourage cocaine seeking and abuse. These compounds would be excellent drug candidates for the development of pharmacological treatment for cocaine addiction.

描述（由申请人提供）：可卡因滥用和成瘾仍然是世界上一个严重的问题。目前，这种精神障碍尚无有效的药理治疗。我们的长期目标是了解可卡因成瘾的机制，以开发对这种疾病的有效治疗方法。可卡因具有三个已知的高亲和力靶标：多巴胺（DA）转运蛋白（DAT），5-羟色胺（5HT）转运蛋白（SERT）和去甲肾上腺素（NE）转运蛋白（NE）。当可卡因进入大脑时，它会阻止所有三个转运蛋白，从而增加了各个大脑区域的细胞外DA，5HT和NE，从而产生复杂的可卡因作用。研究每个转运蛋白的作用的一种方法是通过删除单个转运蛋白产生基因敲除小鼠。这种方法的潜在问题是自适应变化以补偿关键转运蛋白的完全去除可能会显着改变奖励途径。我们正在采用另一种方法。我们正在产生携带一种转运蛋白突变体的敲入小鼠系，该转运蛋白突变体对可卡因抑制不敏感，同时保持功能性单胺摄取。我们已经产生了一条载有可卡因不敏感的DAT突变体的敲门小鼠线，该突变体保留了大量摄取活性。在这些小鼠中，可卡因不再产生奖励，这表明DAT封锁是可卡因奖励所必需的。但是，DAT突变小鼠没有提供有关可卡因效应中净和SERT的作用的信息。拟议研究的具体目的是（1）构建功能性但对可卡因抑制不敏感的SERT和网的突变体；（2）用可卡因不敏感的转运蛋白突变体代替了用SERT或NET生成2种小鼠线；（3）分析可卡因反应通过敲门小鼠。这项研究将告诉我们净或SERT封锁是可卡因奖励是否也是必需的，还是增强或抑制可卡因奖励。关于DA，5HT和NE系统如何调节可卡因奖励和厌恶的精确知识可能表明潜在的药物目标来调节可卡因奖励和厌恶的强度和动力学。可卡因引起的欣快感和延长可卡因烦躁不安的化合物可能会阻止可卡因寻求和滥用。这些化合物将是用于开发可卡因成瘾药理治疗的出色药物。