Institute of Pharmacology and Therapeutics, Biomedical Institute for Research in Light and Image, Faculty of Medicine, University of Coimbra, Subunit 1-Polo 3, Azinhaga de Santa Comba, Celas, 3000-354 Coimbra, Portugal.
Neurotox Res. 2011 Jan;19(1):94-101. doi: 10.1007/s12640-009-9143-9. Epub 2009 Dec 22.
Methamphetamine (METH) abuse and addiction present a major problem in the United States and globally. Oxidative stress associated with exposure to METH mediates to the large extent METH-evoked neurotoxicity. While there are currently no medications approved for treating METH addiction, its pharmacology provides opportunities for potential pharmacotherapeutic adjuncts to behavioral therapy in the treatment of METH addiction. Opioid receptor agonists can modulate the activity of dopamine neurons and could, therefore, modify the pharmacodynamic effects of METH in the dopaminergic system. Efficacy of the adjunctive medication with buprenorphine has been demonstrated in the treatment of cocaine addiction extending beyond opiate addiction. We investigated the interactions of morphine (10 mg/kg) and buprenorphine (0.01 and 10 mg/kg) with METH (2 mg/kg) affecting striatal dopaminergic transmission. The extracellular concentration of dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined using brain microdialysis coupled with high performance liquid chromatography with electrochemical detection (HPLC-ED) in the caudate nucleus of adult, awake, male Sprague-Dawley rats. Compared to METH alone, extracellular DA release was prolonged for 140 min without changes in DA peak-effect by combined treatment with morphine/METH. Morphine did not change DOPAC efflux evoked by METH. On the other hand, both buprenorphine doses attenuated the METH-induced DA peak-effect. However, whereas high buprenorphine dose extended DA outflow for 190 min, the low-dose abbreviated DA release. High buprenorphine dose also shortened METH-induced decrease in DOPAC efflux. Data confirm that opiates modulate dopaminergic neurotransmission evoked by METH. Alteration of dopaminergic response to METH challenge under buprenorphine may suggest effectiveness of buprenorphine treatment in METH addiction.
甲基苯丙胺（METH）滥用和成瘾在美国和全球范围内都是一个主要问题。与接触 METH 相关的氧化应激在很大程度上介导了 METH 引起的神经毒性。虽然目前没有批准用于治疗 METH 成瘾的药物，但它的药理学为治疗 METH 成瘾的行为治疗提供了潜在的药物治疗辅助手段的机会。阿片受体激动剂可以调节多巴胺神经元的活性，因此可以改变 METH 在多巴胺能系统中的药效学效应。在治疗可卡因成瘾方面，丁丙诺啡辅助药物的疗效已经超出了阿片类药物成瘾的范围。我们研究了吗啡（10mg/kg）和丁丙诺啡（0.01 和 10mg/kg）与 METH（2mg/kg）联合作用对纹状体多巴胺能传递的影响。使用脑微透析与高效液相色谱-电化学检测（HPLC-ED）相结合，在成年雄性 Sprague-Dawley 大鼠尾状核中测定多巴胺（DA）及其代谢物 3,4-二羟基苯乙酸（DOPAC）的细胞外浓度。与单独使用 METH 相比，联合使用吗啡/METH 可使细胞外 DA 释放延长 140min，而不改变 DA 峰值效应。吗啡不会改变 METH 引起的 DOPAC 外排。另一方面，两种丁丙诺啡剂量均减弱了 METH 引起的 DA 峰值效应。然而，高丁丙诺啡剂量将 DA 外流延长 190min，而低剂量则缩短了 DA 释放。高丁丙诺啡剂量还缩短了 METH 引起的 DOPAC 外排减少。数据证实阿片类药物调节 METH 引起的多巴胺能神经传递。丁丙诺啡下 METH 挑战引起的多巴胺反应的改变可能表明丁丙诺啡治疗 METH 成瘾的有效性。
