Cocaine and monoamine transporters

可卡因滥用和成瘾仍然是世界上的一个严重问题。目前，没有有效的 药物治疗这种精神疾病。我们的长期目标是了解 可卡因成瘾，以开发有效的治疗这种疾病。科克伦有三个已知的高 亲和靶点，多巴胺（DA）转运蛋白（DAT），5-羟色胺（5 HT）转运蛋白（SERT），和 去甲肾上腺素（NE）转运蛋白（NET）。当可卡因进入大脑时，它会阻断所有三种转运蛋白， 因此增加了不同脑区的细胞外DA、5 HT和NE，导致复杂的可卡因效应。 研究每种转运蛋白作用的一种方法是用单个转运蛋白产生敲除小鼠 的页面不存在或这种方法的潜在问题是，自适应变化，以补偿完整的 去除关键转运蛋白可能会显著改变奖赏途径。我们雇用了一名 替代方法。我们正在产生基因敲入的小鼠品系，它们携带一种转运蛋白突变体， 对可卡因抑制不敏感，同时保持功能性单胺摄取。我们创造了一个 携带可卡因不敏感DAT突变体的敲入小鼠系，该突变体保留了大量的摄取活性。在 在这些小鼠中，可卡因不再产生奖励，这表明DAT阻断对于可卡因是必要的。 奖励然而，DAT突变小鼠没有提供关于NET和SERT在 可卡因的影响。本研究的具体目的是（1）构建SERT和NET的突变体， 有功能但对可卡因抑制不敏感;（2）产生2个具有SERT或NET的小鼠系 用可卡因不敏感的转运蛋白突变体代替;和（3）用可卡因不敏感的转运蛋白突变体分析可卡因应答。 基因敲入小鼠这项研究将告诉我们NET或SERT阻断是否也是可卡因奖励所必需的， 或者增强或抑制可卡因的奖赏关于DA、5 HT和NE系统如何调节 可卡因的奖赏和厌恶可能表明潜在的药物靶点，以调节强度和动力学， 可卡因奖励和厌恶抑制可卡因引起的欣快感并延长可卡因的化合物 烦躁不安可能会阻碍可卡因的寻求和滥用。这些化合物将是很好的药物 开发可卡因成瘾药物治疗的候选人。

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 necessaryfor 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.