Cocaine mechanisms: Enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions
Cocaine mechanisms: Enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions
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DOI：
10.1016/s0306-4522(02)00379-2
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发表时间：
2002-01-01
期刊：
影响因子：
3.3
通讯作者：
Uhl, GR
中科院分区：
文献类型：
--
作者：
Hall, FS;Li, XF;Uhl, GR
可卡因阻断神经元质膜转运蛋白对多巴胺、5-羟色胺和去甲肾上腺素的摄取，在人类中产生主观效应，既有欣快/奖励，也有恐惧、紧张和厌恶。这些转运蛋白基因敲除的小鼠显示可卡因奖励，表现为可卡因的位置偏好，至少与野生型值一样大。去甲肾上腺素和5-羟色胺受体敲除甚至显示出增强的可卡因奖励。这些观察结果的一种解释可能是，可卡因通过阻断野生型小鼠的血清素或去甲肾上腺素受体而产生厌恶或快感缺失效应，这些效应在血清素或去甲肾上腺素受体敲除后被消除，从而增加可卡因的净奖励。去除一种转运蛋白的适应性也可能改变阻断其余转运蛋白的回报价。为了验证这些想法，在单或多个转运蛋白基因敲除小鼠中检测了阻断血清素转运蛋白（氟西汀）、去甲肾上腺素转运蛋白（尼索西汀）或所有三种转运蛋白（可卡因）的药物。氟西汀和尼索西汀在几种基因敲除中获得了在野生型小鼠中未观察到的奖励特性。将5-羟色胺转运体基因敲除与去甲肾上腺素转运体基因敲除相结合，可以显著增强可卡因的奖赏效应，这些数据和以前的数据都证明了5-羟色胺和去甲肾上腺素转运体基因的阻断可以增加可卡因的净奖赏效价。他们确定了神经适应，这可能有助于解释多巴胺和5-羟色胺转运蛋白敲除小鼠对可卡因奖励的保留。它们与新出现的假设一致，即可卡因的三个主要脑分子靶点的作用各自对野生型小鼠中的可卡因奖励和可卡因厌恶提供不同的贡献，并且这种平衡在没有多巴胺、去甲肾上腺素或5-羟色胺转运蛋白的小鼠中发生变化。由Elsevier Science Ltd代表IBRO发布。
Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine, serotonin and norepinephrine, producing subjective effects in humans that are both euphoric/rewarding and also fearful, jittery and aversive. Mice with gene knockouts of each of these transporters display cocaine reward, manifest by cocaine place preferences that are at least as great as wildtype values. Norepinephrine and serotonin receptor knockouts even display enhanced cocaine reward. One explanation for these observations could be that cocaine produces aversive or anhedonic effects by serotonin or norepinephrine receptor blockade in wildtype mice that are removed in serotonin or norepinephrine receptor knockouts, increasing net cocaine reward. Adaptations to removing one transporter could also change the rewarding valence of blocking the remaining transporters. To test these ideas, drugs that block serotonin transporter (fluoxetine), norepinephrine transporter (nisoxetine) or all three transporters (cocaine) were examined in single- or multiple-transporter knockout mice. Fluoxetine and nisoxetine acquire rewarding properties in several knockouts that are not observed in wildtype mice. Adding serotonin transporter knockout to norepinephrine transporter knockouts dramatically potentiates cocaine reward.These and previous data provide evidence that serotonin and norepinephrine transporter blockade can contribute to the net rewarding valence of cocaine. They identify neuroadaptations that may help to explain the retention of cocaine reward by dopamine and serotonin transporter knockout mice. They are consistent with emerging hypotheses that actions at the three primary brain molecular targets for cocaine each provide distinct contributions to cocaine reward and cocaine aversion in wildtype mice, and that this balance changes in mice that develop without dopamine, norepinephrine or serotonin transporters. Published by Elsevier Science Ltd on behalf of IBRO.