Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine.
Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine.
复制标题
去甲肾上腺素合成的遗传或药理学阻断会增强甲基苯丙胺的神经化学、行为和神经毒性作用。
DOI：
10.1111/j.1471-4159.2007.05145.x
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发表时间：
2008
影响因子：
4.7
通讯作者：
Fornai,Francesco
中科院分区：
文献类型：
--
作者：
Weinshenker,David;Ferrucci,Michela;Busceti,CarlaL;Biagioni,Francesca;Lazzeri,Gloria;Liles,LCameron;Lenzi,Paola;Pasquali,Livia;Murri,Luigi;Paparelli,Antonio;Fornai,Francesco
N-(2-氯乙基)-N-乙基-2-溴苯甲胺(DSP-4)损毁蓝斑是大脑的主要去甲肾上腺素能核，加重了精神刺激剂甲基苯丙胺对黑质纹状体多巴胺(DA)终末的损害。然而，由于去甲肾上腺素能终末含有其他神经调节剂和去甲肾上腺素(NA)转运体，可能起到神经保护缓冲的作用，因此尚不清楚这种甲基神经毒性的增强是由于去甲肾上腺素能神经支配的丧失还是NA本身的丧失所致。我们通过比较冰毒对患有去甲肾上腺素能损伤(DSP4)的小鼠和那些去甲肾上腺素能终末完整但特别缺乏NA(遗传或急性药物阻断NA生物合成酶多巴胺β-羟基酶；DBH)的小鼠的影响，阐述了NA的特定作用。我们发现，DBH(DBH−/−小鼠)的基因缺失和DBH抑制剂(Fusaric Acid)对野生型小鼠的急性治疗概括了DSP4损伤对冰毒反应的影响。NA耗竭的三种方法均可增强纹状体DA的释放、细胞外氧化应激(通过DA和2，3-二羟基苯甲酸的活体微透析测量)，以及重复给药后的行为刻板印象。这些效应伴随着纹状体DA神经元终末损伤的恶化和中等棘神经元的超微结构变化。我们得出结论，NA本身具有神经保护作用，在纹状体DA终末对冰毒的神经化学、行为和神经毒性效应的敏感性中起着重要作用。
N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP‐4) lesions of the locus coeruleus, the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP‐4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine β‐hydroxylase; DBH). We found that genetic deletion of DBH (DBH−/− mice) and acute treatment of wild‐type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP‐4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured byin vivomicrodialysis of DA and 2,3‐dihydroxybenzoic acid), and behavioral stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioral, and neurotoxic effects of METH.