Molecular mechanisms underlying the rewarding effects of cocaine
Molecular mechanisms underlying the rewarding effects of cocaine
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DOI：
10.1196/annals.1316.006
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Uhl, GR
中科院分区：
文献类型：
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作者：
Hall, FS;Sora, I;Uhl, GR
最初令人惊讶的观察结果是，可卡因在多巴胺转运蛋白（DAT）敲除（KO）小鼠中保留了其奖励作用，这促使我们的实验室研究了其他单胺能基因缺失对可卡因奖励的影响。我们最初解决这个问题的方法是将DAT KO小鼠与血清素转运蛋白（SERT） KO小鼠结合，制成DAT/ SERT KO小鼠。根据条件位置偏好（CPP）范式的评估，这些击倒组合消除了可卡因奖励。我们还发现证据表明，在没有DAT的情况下，血清素（SERT）和去甲肾上腺素（NET）转运体更大程度地参与可卡因奖励。NET和SERT阻滞剂（尼西汀和氟西汀）在DAT KO小鼠中产生显著的CPPs，但在野生型（WT）小鼠中没有。DAT/SERT联合KO小鼠中可卡因CPP的显著消除与我们在NET/SERT联合敲除小鼠中发现的效果形成鲜明对比，后者显示出可卡因奖励增加，并且最近的报道表明DAT/NET联合KO小鼠保留了大量可卡因CPP。总的来说，这些研究表明了几个单胺系统基因的重要要求，以充分解释可卡因奖励，特别是那些由多巴胺和血清素系统表达的基因。
The initially surprising observation that cocaine retains its rewarding effects in dopamine transporter (DAT) knockout (KO) mice led our laboratory to examine the effects of deletion of other monoaminergic genes on cocaine reward. Our initial approach to this problem was to combine DAT KO mice with serotonin transporter (SERT) KO mice to make combined DAT/ SERT KO mice. The combination of these knockouts eliminates cocaine reward as assessed in the conditioned place preference (CPP) paradigm. We have also identified evidence that, in the absence of DAT, there is greater participation in cocaine reward by serotonin (SERT) and norepinephrine (NET) transporters. Both NET and SERT blockers (nisoxetine and fluoxetine) produced significant CPPs in DAT KO mice, but not in wild-type (WT) mice. The striking elimination of cocaine CPP in combined DAT/SERT KO mice contrasts with effects that we have identified in combined NET/SERT knockout mice, which display increases in cocaine reward, and with recent reports that suggest that DAT/NET combined KOs retain substantial cocaine CPP. Overall, these studies indicate important requirements for several monoaminergic system genes to fully explain cocaine reward, in particular those expressed by dopamine and serotonin systems.