Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users
Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users
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DOI：
10.1016/j.neuropharm.2008.04.019
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发表时间：
2008-07-01
影响因子：
4.7
通讯作者：
Kish, Stephen J.
中科院分区：
文献类型：
--
作者：
Frankel, Paul S.;Alburges, Mario E.;Kish, Stephen J.
针对脑神经肽系统治疗可卡因成瘾的治疗药物(如K阿片激动剂)的开发兴趣基于动物数据，显示神经肽、脑多巴胺和可卡因之间的相互作用。在这项大脑尸检研究中，我们的主要目的是通过放射免疫分析来确定强啡肽和其他神经肽(如甲脑啡肽、神经降压素和P物质)的水平是否像动物发现所预测的那样，在人类慢性可卡因使用者(n=12)的富含多巴胺的尾核、壳核和伏隔核(n=17)中高于匹配的对照组受试者(n=17)。变化仅限于尾状核强啡肽免疫反应性显著增加(+92%)，尾状核神经降压素降低(-49%)，壳核强啡肽有增加趋势(+75%)。在其他被检查的皮质下/大脑皮质区域，强啡肽水平正常，除了腹侧苍白球(+346%)，而大脑皮质的脑啡肽水平普遍下降，神经降压素发生不同的变化。我们的发现与动物数据相反，人类可卡因吸毒者的其他纹状体神经肽没有增加，这可以用人类吸毒者和动物模型之间的模式和偶然性的差异来解释。然而，人类强啡肽的观察结果与动物的观察结果一致，表明在长期接触纹状体和腹侧苍白球药物后，强啡肽系统上调，表现为神经肽水平升高。我们的尸检脑数据表明，人类可卡因使用者参与了纹状体强啡肽系统，这应该会增加人们对测试与强啡肽相关的新疗法治疗可卡因成瘾的兴趣。(C)2008爱思唯尔有限公司。保留所有权利。
Interest in development of therapeutics targeting brain neuropeptide systems for treatment of cocaine addiction (e.g., K opioid agonists) is based on animal data showing interactions between the neuropeptides, brain dopamine, and cocaine. In this autopsied brain study, our major objective was to establish by radioimmunoassay whether levels of dynorphin and other neuropeptides (e.g., metenkephalin, neurotensin and substance P) are increased in the dopamine-rich caudate, putamen, and nucleus accumbens of human chronic cocaine users (n = 12) vs. matched control subjects (n = 17) as predicted by animal findings. Changes were limited to markedly increased dynorphin immunoreactivity in caudate (+92%), decreased caudate neurotensin (-49%), and a trend for increased dynorphin (+75%) in putamen. in other examined subcortical/cerebral cortical areas dynorphin levels were normal with the striking exception of the ventral pallidum (+346%), whereas cerebral cortical metenkephalin levels were generally decreased and neurotensin variably changed. Our finding that, in contradistinction to animal data, the other striatal neuropeptides were not increased in human cocaine users could be explained by differences in pattern and contingency between human drug users and the animal models. However, the human dynorphin observations parallel well animal findings and suggest that the dynorphin system is upregulated, manifested as elevated neuropeptide levels, after chronic drug exposure in striatum and ventral pallidum. Our postmortem brain data suggest involvement of striatal dynorphin systems in human cocaine users and should add to the interest in the testing of new dynorphin-related therapeutics for the treatment of cocaine addiction. (c) 2008 Elsevier Ltd. All rights reserved.