Fornai Francesco, Alessandrì Maria Grazia, Torrac Maria Tilde, Bassi Lucia, Scalori Vera, Corsini Giovanni Umberto
Institute of Pharmacology, School of Medicine, University of Pisa, Via Roma 55, 56100-I, Pisa, ItalyIRCCS Stella Maris-INPE, University of Pisa, Pisa, Italy.
Ann N Y Acad Sci. 1998 May;844(1):166-177. doi: 10.1111/j.1749-6632.1998.tb08231.x.
Noradrenergic (NE) neurons belonging to the locus coeruleus (LC), much more than the A1 and A2 NE areas, are lost in Parkinson's disease (PD). In this study, we reproduced the selective pattern of NE loss involving axons arising from the LC using the selective neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (50 mg/kg). In these experimental conditions, we investigated whether NE loss potentiates methamphetamine-induced striatal dopamine (DA) depletion in mice and in rats. Administration of a moderate dose of methamphetamine to C57B1/6N mice or Sprague-Dawley rats produced only a partial striatal DA depletion 7 days after drug administration. Pretreatment with DSP-4, in both animal species, significantly enhanced methamphetamine-induced striatal DA depletion. Administration of a lower dose of methamphetamine did not decrease striatal DA levels when injected alone, but produced a significant decrease in striatal DA when given to DSP-4-pretreated rodents. Moreover, we found that agents reducing the noradrenergic activity (i.e., the alpha-2 agonist clonidine) enhanced, whereas alpha-2 antagonists decreased, methamphetamine toxicity. Enhancement of methamphetamine toxicity did not occur if the noradrenergic lesion was produced 12 hr after methamphetamine administration. By contrast, exacerbation of methamphetamine toxicity in NE-depleted animals was accompanied by increased extracellular DA levels measured with brain dialysis and by a more severe acute DA depletion measured in striatal homogenates.
与A1和A2去甲肾上腺素能（NE）区域相比，帕金森病（PD）中属于蓝斑（LC）的NE能神经元损失更为严重。在本研究中，我们使用选择性神经毒素N-（-2-氯乙基）-N-乙基-2-溴苄胺（DSP-4）（50mg/kg）重现了涉及源自LC的轴突的NE选择性损失模式。在这些实验条件下，我们研究了NE损失是否会增强甲基苯丙胺诱导的小鼠和大鼠纹状体多巴胺（DA）耗竭。给C57B1/6N小鼠或Sprague-Dawley大鼠施用中等剂量的甲基苯丙胺，在给药7天后仅导致部分纹状体DA耗竭。在这两种动物中，用DSP-4预处理可显著增强甲基苯丙胺诱导的纹状体DA耗竭。单独注射较低剂量的甲基苯丙胺不会降低纹状体DA水平，但给予DSP-4预处理的啮齿动物时会导致纹状体DA显著降低。此外，我们发现降低去甲肾上腺素能活性的药物（即α-2激动剂可乐定）会增强甲基苯丙胺毒性，而α-2拮抗剂则会降低其毒性。如果在甲基苯丙胺给药12小时后产生去甲肾上腺素能损伤，则不会出现甲基苯丙胺毒性增强的情况。相比之下，NE耗竭动物中甲基苯丙胺毒性的加剧伴随着脑透析测量的细胞外DA水平升高以及纹状体匀浆中更严重的急性DA耗竭。
