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，还没有有效的 对这种精神疾病的药物治疗。我们的长期目标是了解 为了开发治疗这一疾病的有效方法，我们正在努力消除可卡因成瘾。可卡因有三种已知的快感 亲和力靶标、多巴胺(DA)转运体(DAT)、5-羟色胺(5-羟色胺)转运体(SERT)和 去甲肾上腺素(NE)转运体(净)。当可卡因进入大脑时，它会阻止所有三种转运蛋白 从而增加不同脑区的细胞外多巴胺、5-羟色胺和去甲肾上腺素，导致复杂的可卡因效应。 研究每个转运蛋白作用的一种方法是用单个转运蛋白产生基因敲除小鼠 已删除。这种方法的潜在问题是，自适应变化来补偿 移除关键转运蛋白可能会显著改变奖赏途径。我们正在雇用一名 另一种方法。我们正在产生一种携带转运蛋白突变体的敲入鼠系 对可卡因抑制不敏感，同时保持功能性单胺摄取。我们已经生成了一个 携带对可卡因不敏感的DAT突变体的敲入小鼠品系，该突变保留了大量的摄取活性。在……里面 在这些小鼠中，可卡因不再产生奖赏，这表明DAT阻断是可卡因所必需的 奖励。然而，DAT突变小鼠并不提供有关Net和SERT在 可卡因效应。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)用它们的SERT或Net产生2个小鼠系 替换为对可卡因不敏感的转运蛋白突变体；以及(3)通过 敲进去的老鼠。这项研究将告诉我们，网络或SERT封锁是否也是可卡因奖励所必需的， 或者它会增强或抑制可卡因的奖励。关于DA、5HT和NE系统如何调制的精确知识 可卡因的奖赏和厌恶可能提示潜在的药物靶点来调节 可卡因的奖赏和厌恶。抑制可卡因引起的快感并延长可卡因的化合物 焦虑症可能会阻止可卡因的寻找和滥用。这些化合物将是极好的药物。 可卡因成瘾药物治疗发展的候选者。

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.