Similitude in Methamphetamine-Induced Neuroadaptations Across Susceptibility and Chronic Drug Exposure Paradigms.
Similitude in Methamphetamine-Induced Neuroadaptations Across Susceptibility and Chronic Drug Exposure Paradigms.
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DOI：
10.1016/j.biopsych.2017.02.1178
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发表时间：
2017-06-01
影响因子：
10.6
通讯作者：
Scofield MD
中科院分区：
文献类型：
--
作者：
Scofield MD
Szumlinski等人的研究(1)在本期《生物精神病学》上调查了甲基苯丙胺成瘾的分子相关性，重点是伏隔核中的谷氨酸能系统。这篇文章的标题呼应了经典的意大利西部电影，它的独特之处在于，它在易受甲基苯丙胺成瘾的人群的伏隔谷氨酸系统的改变状态以及长期接触甲基苯丙胺的人群中发现了共性。在研究的第一部分，Szumlinski等人(1)使用了一种注入甲基苯丙胺的饮用水范例，即小鼠口服自我给药。通过选择性的小鼠繁殖，出现了两类动物，一类是喝更多溶液的动物(高剂量饮用甲基苯丙胺[MAHDR])，另一类是喝得少的(低剂量饮用甲基苯丙胺[MALDR])。这种分裂建立了一个平台，以调查谷氨酸信号的变化，这些变化可能是甲基苯丙胺成瘾或成瘾易感性的基础，在整个研究过程中，这一策略在几个不同的排列中使用。研究人员发现，与MALDR动物相比，MAHDR动物的基础细胞外谷氨酸水平更高，伏隔核中代谢性谷氨酸受体5(MGluR5)和Hmer 2a/b的表达增加。这一结果与Gass等人的研究有很好的共鸣。(2)研究表明，mGluR5的拮抗作用抑制了恢复的甲基苯丙胺寻找。此外，这篇文章提供的数据与同一小组以前的研究很好地吻合，证明Hmer 2a/b参与了与药物有关的行为(3，4)。最后，Hmer 2和mGluR5基因敲除的动物进一步支持了这些蛋白质在成瘾中的作用(5，6)。随着Szumlinski等人(1)阐明了这两种动物的伏隔谷氨酸系统的差异，他们的研究提出了一系列有趣的问题，关于这些蛋白质表达的变化是如何发生的。显而易见的是，这肯定至少部分归因于MAHDR动物较高的药物暴露水平。因此，药物诱导的蛋白质表达变化开始发生在暴露于较高水平甲基苯丙胺的受试者中，然后很可能通过某种形式的表观遗传印记传递给后代(7)。这为未来的研究提供了可能性，这些研究旨在研究组蛋白修饰在MAHDR和MALDR动物的伏隔核mGluR5和Hmer 2a/b基因座上的可能差异。如果在这些基因上发现了组蛋白修饰的差异，逆转它们是否会将MAHDR对象变成MALDR对象？这些差异是男性还是女性受试者所特有的？
The study by Szumlinski et al.(1) in this issue of Biological Psychiatry investigates molecular correlates of methamphetamine addiction, with a focus on the glutamatergic system in the nucleus accumbens. This article, whose title echoes that of the classic spaghetti western film, is unique in that it finds commonality in the altered states of the accumbens glutamate system of populations susceptible to methamphetamine addiction as well as in populations chronically exposed to the drug.In the first part of the study, Szumlinski et al.(1) employ a methamphetamine-infused drinking water paradigm whereby mice orally self-administer the drug. Through selective mouse breeding, two subsets of animals emerge, those that drink more of the solution (methamphetamine high drinking [MAHDR]) and those that drink less (methamphetamine low drinking [MALDR]). This split establishes a platform to investigate alterations in glutamate signaling that may underlie methamphetamine addiction or vulnerability to addiction, a strategy used throughout the study in several different permutations. The investigators find that compared with MALDR animals, the MAHDR animals display a higher level of basal extracellular glutamate and increased expression of metabotropic glutamate receptor 5 (mGluR5) and Homer2a/b in the nucleus accumbens. This result resonates well with the Gass et al.(2) study that demonstrated that antagonism of mGluR5 inhibits reinstated methamphetamine seeking. Furthermore, the data presented in the current article fit well with previous studies from the same group demonstrating the involvement of Homer2a/b in drug-related behaviors (3, 4). Finally, knockout animals for Homer2 and mGluR5 further support a role for these proteins in addiction (5, 6). As Szumlinski et al.(1) elucidate differences in the accumbens glutamate systems of these two populations of animals, their study brings to mind an intriguing set of questions regarding how these changes in protein expression are enacted. It is immediately apparent that it must be due, at least in part, to the higher levels of drug exposure in MAHDR animals. It follows then that drug-induced alterations in protein expression start to take place in subjects exposed to higher levels of methamphetamine and are then likely passed onto progeny via some form of epigenetic imprinting (7). This raises the possibility for future studies aimed at investigating possible differences in histone protein modifications at the mGluR5 and Homer2a/b loci in the nucleus accumbens of MAHDR versus MALDR animals. If differences in histone modifications at these genes were found, could reversing them turn an MAHDR subject into an MALDR subject? Would these differences be specific to male or female subjects?
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影响因子：
16.2
作者：
Szumlinski, KK;Dehoff, MH;Kalivas, PW
通讯作者：
Kalivas, PW
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5.3
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Szumlinski, KK;Lominac, KD;Kalivas, PW
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作者：
Vassoler, Fair M.;White, Samantha L.;Schmidt, Heath D.;Sadri-Vakili, Ghazaleh;Pierce, R Christopher
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Pierce, R Christopher