Hall F S, Li X F, Sora I, Xu F, Caron M, Lesch K P, Murphy D L, Uhl G R
Molecular Neurobiology Branch, NIDA-IRP, NIH, Box 5180, Baltimore, MD 21224, USA.
Neuroscience. 2002;115(1):153-61. doi: 10.1016/s0306-4522(02)00379-2.
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.
可卡因可阻断神经元质膜转运体对多巴胺、5-羟色胺和去甲肾上腺素的摄取，在人体产生主观效应，既有欣快感/奖赏感，也有恐惧感、紧张不安感和厌恶感。对这些转运体进行基因敲除的小鼠表现出可卡因奖赏效应，表现为可卡因位置偏爱，其程度至少与野生型小鼠相同。去甲肾上腺素和5-羟色胺受体敲除小鼠甚至表现出增强的可卡因奖赏效应。对这些观察结果的一种解释可能是，在野生型小鼠中，可卡因通过阻断5-羟色胺或去甲肾上腺素受体产生厌恶或快感缺失效应，而在5-羟色胺或去甲肾上腺素受体敲除小鼠中这些效应被消除，从而增加了可卡因的净奖赏效应。去除一种转运体的适应性变化也可能改变阻断其余转运体的奖赏效价。为了验证这些观点，研究人员在单转运体或多转运体敲除小鼠中检测了阻断5-羟色胺转运体（氟西汀）、去甲肾上腺素转运体（尼索西汀）或所有三种转运体（可卡因）的药物。氟西汀和尼索西汀在几种敲除小鼠中获得了在野生型小鼠中未观察到的奖赏特性。将5-羟色胺转运体敲除与去甲肾上腺素转运体敲除相结合，可显著增强可卡因奖赏效应。这些数据以及之前的数据表明，阻断5-羟色胺和去甲肾上腺素转运体可影响可卡因的净奖赏效价。它们确定了一些神经适应性变化，这可能有助于解释多巴胺和5-羟色胺转运体敲除小鼠对可卡因奖赏效应的保留。它们与新出现的假说一致，即在野生型小鼠中，作用于可卡因的三个主要脑部分子靶点的行为各自对可卡因奖赏和可卡因厌恶有不同贡献，而在没有多巴胺、去甲肾上腺素或5-羟色胺转运体的小鼠中这种平衡会发生变化。
