Cocaine hydrolase blocks cocaine-induced dopamine transporter trafficking to the plasma membrane.
Cocaine hydrolase blocks cocaine-induced dopamine transporter trafficking to the plasma membrane.
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DOI：
10.1111/adb.13089
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发表时间：
2022-01
影响因子：
3.4
通讯作者：
Zheng F
中科院分区：
文献类型：
--
作者：
Deng J;Kim K;Zheng X;Shang L;Zhan CG;Zheng F
可卡因通过神经元细胞质膜上的多巴胺转运体（DAT）阻断多巴胺摄取，并且因此产生高并诱导DAT运输到质膜，这有助于药物寻求或渴望。在这项研究中，我们首先检查了可卡因诱导的DAT运输和大鼠多动症的剂量依赖性，证明了10 mg/kg或更高剂量的可卡因导致大多数DAT重新分布到质膜，同时诱导大鼠显著多动症。然而，施用5 mg/kg可卡因（i. p.）在大鼠中没有显著诱导DAT运输或活动过度。因此，阈值（i. p.）可显著诱导DAT运输或活动过度的可卡因剂量应在5和10 mg/kg之间。这些数据表明，当可卡因剂量高到足以诱导显著的活动过度时，它也可以显著诱导DAT向质膜的运输。此外，诱导显著活动过度和DAT运输所需的阈值脑可卡因浓度估计为~2.0±0.8 μg/g。特别地，对于可卡因滥用的治疗，先前的研究表明，外源性可卡因代谢酶，例如CocH 3-Fc（M3），可以有效地阻断可卡因诱导的多动症。然而，尚不清楚酶是否也能有效阻止可卡因诱导的DAT向质膜的运输。这项研究首次证明，即使致命剂量为60 mg/kg可卡因（腹腔注射），该酶也能够有效阻止可卡因到达大脑并因此有效地防止可卡因诱导的生理效应，例如活动过度和DAT运输。
Cocaine blocks dopamine uptake via dopamine transporter (DAT) on plasma membrane of neuron cells and, as a result, produces the high and induces DAT trafficking to plasma membrane which contributes to the drug seeking or craving. In this study, we first examined the dose dependence of cocaine-induced DAT trafficking and hyperactivity in rats, demonstrating that cocaine at an i.p. dose of 10 mg/kg or higher led to redistribution of most DAT to the plasma membrane while inducing significant hyperactivity in rats. However, administration of 5 mg/kg cocaine (i.p.) did not significantly induce DAT trafficking or hyperactivity in rats. So, the threshold (i.p.) dose of cocaine which can significantly induce DAT trafficking or hyperactivity should be between 5 and 10 mg/kg. These data suggest that when a cocaine dose is high enough to induce significant hyperactivity, it can also significantly induce DAT trafficking to the plasma membrane. Further, the threshold brain cocaine concentration required to induce significant hyperactivity and DAT trafficking was estimated to be ~2.0±0.8 μg/g. Particularly, for treatment of cocaine abuse, previous studies demonstrated that an exogenous cocaine-metabolizing enzyme, e.g. CocH3-Fc(M3), can effectively block cocaine-induced hyperactivity. However, it was unknown whether an enzyme could also effectively block cocaine-induced DAT trafficking to the plasma membrane. This study demonstrates, for the first time, that the enzyme is also capable of effectively blocking cocaine from reaching the brain even with a lethal dose of 60 mg/kg cocaine (i.p.) and, thus, powerfully preventing cocaine-induced physiological effects such as the hyperactivity and DAT trafficking.
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与奖励相关行为中的多巴胺信号传导。
影响因子：
3.5
作者：
Baik JH
通讯作者：
Baik JH
DOI：
10.1073/pnas.0507332102
发表时间：
2005-11-15
影响因子：
11.1
作者：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
3.6
作者：
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通讯作者：
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