Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter
Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter
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DOI：
10.1073/pnas.0600905103
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发表时间：
2006-06-13
影响因子：
11.1
通讯作者：
Gu, Howard H.
中科院分区：
文献类型：
--
作者：
Chen, Rong;Tilley, Michael R.;Gu, Howard H.
可卡因有三个已知的高亲和力靶点：多巴胺转运蛋白（DAT）、5-羟色胺转运蛋白（SERT）和去甲肾上腺素转运蛋白（NET）。几十年的研究支持多巴胺（DA）的假设，即DAT的阻断和随后的细胞外DA的增加主要介导可卡因的奖励和强化。与预期相反，DAT敲除（DAT-KO）小鼠和SERT或NET敲除小鼠仍然自我施用可卡因和/或显示条件性位置偏好（CPP）可卡因，这导致重新评估DA假说和冗余奖励途径的建议。为了研究DAT在可卡因奖赏中的作用，我们产生了一个敲入小鼠系，该小鼠系携带对可卡因不敏感的功能性DAT。在这些小鼠中，可卡因抑制自发活动，没有提高细胞外DA在丘脑核，并没有产生奖励测量的CPP。这一结果表明，DAT的封锁是必要的可卡因奖励小鼠的功能DAT。这种小鼠模型是独特的，因为它是专门设计来区分DAT的作用，从可卡因诱导的生化和行为效应的NET和SERT的作用。
There are three known high-affinity targets for cocaine: the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). Decades of studies support the dopamine (DA) hypothesis that the blockade of DAT and the subsequent increase in extracellular DA primarily mediate cocaine reward and reinforcement. Contrary to expectations, DAT knockout (DAT-KO) mice and SERT or NET knockout mice still self-administer cocaine and/or display conditioned place preference (CPP) to cocaine, which led to the reevaluation of the DA hypothesis and the proposal of redundant reward pathways. To study the role of DAT in cocaine reward, we have generated a knockin mouse line carrying a functional DAT that is insensitive to cocaine. In these mice, cocaine suppressed locomotor activity, did not elevate extracellular DA in the nucleus accumbens, and did not produce reward as measured by CPP. This result suggests that blockade of DAT is necessary for cocaine reward in mice with a functional DAT. This mouse model is unique in that it is specifically designed to differentiate the role of DAT from the roles of NET and SERT in cocaine-induced biochemical and behavioral effects.