A role for D1 dopamine receptors in striatal methamphetamine-induced neurotoxicity.
A role for D1 dopamine receptors in striatal methamphetamine-induced neurotoxicity.
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DOI：
10.1016/j.neulet.2013.08.039
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发表时间：
2013-10-25
影响因子：
2.5
通讯作者：
Keefe KA
中科院分区：
文献类型：
--
作者：
Friend DM;Keefe KA
接触甲基苯丙胺会对人类和动物模型的多巴胺系统造成长期损害。在这种冰毒诱导的多巴胺能系统损伤中，一个被严重牵连的因素是D1多巴胺(DA)受体的激活。然而，对于研究受体在这种毒性中的作用的研究来说，一个重要的警告是，对D1DA受体的遗传和药物操作也可以缓解冰毒诱导的体温升高。重要的是，冰毒引起的体温过高与神经毒性密切相关，因此，在冰毒暴露期间简单地给动物降温就可以保护动物免受神经毒性的影响。因此，很难确定D1DA受体本身是否在冰毒诱导的神经毒性中发挥重要作用，或者观察到的保护作用是否简单地源于冰毒诱导的体温升高的缓解。为了回答这个重要的问题，本研究在控制冰毒诱导的体温过高的同时，在接触冰毒期间向纹状体内注入了一种D1DA受体拮抗剂。我们发现，即使在维持冰毒诱导的体温升高的情况下，D1DA受体拮抗剂的联合应用也能对抗冰毒诱导的神经毒性，这有力地表明D1DA受体除了在缓解冰毒诱导的体温升高之外，还在冰毒诱导的神经毒性中发挥重要作用。
Methamphetamine (METH) exposure results in long-term damage to the dopamine system in both human METH abusers and animal models. One factor that has been heavily implicated in this METH-induced damage to the dopaminergic system is the activation of D1 Dopamine (DA) receptors. However, a significant caveat to the studies investigating the role of the receptor in such toxicity is that genetic and pharmacological manipulations of the D1 DA receptor also mitigate METH-induced hyperthermia. Importantly, METH-induced hyperthermia is tightly associated with the neurotoxicity, such that simply cooling animals during METH exposure protects against the neurotoxicity. Therefore, it is difficult to determine whether D1 DA receptors per se play an important role in METH-induced neurotoxicity or whether the protection observed simply resulted from a mitigation of METH-induced hyperthermia. To answer this important question, the current study infused a D1 DA receptor antagonist into striatum during METH exposure while controlling for METH-induced hyperthermia. Here we found that even when METH-induced hyperthermia is maintained, the coadministration of a D1 DA receptor antagonist protects against METH-induced neurotoxicity, strongly suggesting that D1 DA receptors play an important role in METH-induced neurotoxicity apart from the mitigation of METH-induced hyperthermia.
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