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Environmental, genetic and epigenetic contributions to cocaine addiction.
Neuropsychopharmacology ( IF 7.6 ) Pub Date : 2018-06-01 , DOI: 10.1038/s41386-018-0008-x
R. Christopher Pierce , Bruno Fant , Sarah E. Swinford-Jackson , Elizabeth A. Heller , Wade H. Berrettini , Mathieu E. Wimmer

Decades of research on cocaine has produced volumes of data that have answered many important questions about the nature of this highly addictive drug. Sadly, none of this information has translated into the development of effective therapies for the treatment of cocaine addiction. This review endeavors to assess the current state of cocaine research in an attempt to identify novel pathways for therapeutic development. For example, risk of cocaine addiction is highly heritable but genome-wide analyses comparing cocaine-dependent individuals to controls have not resulted in promising targets for drug development. Is this because the genetics of addiction is too complex or because the existing research methodologies are inadequate? Likewise, animal studies have revealed dozens of enduring changes in gene expression following prolonged exposure to cocaine, none of which have translated into therapeutics either because the resulting compounds were ineffective or produced intolerable side-effects. Recently, attention has focused on epigenetic modifications resulting from repeated cocaine intake, some of which appear to be heritable through changes in the germline. While epigenetic changes represent new vistas for therapeutic development, selective manipulation of epigenetic marks is currently challenging even in animals such that translational potential is a distant prospect. This review will reveal that despite the enormous progress made in understanding the molecular and physiological bases of cocaine addiction, there is much that remains a mystery. Continued advances in genetics and molecular biology hold potential for revealing multiple pathways toward the development of treatments for the continuing scourge of cocaine addiction.

中文翻译:

环境,遗传和表观遗传对可卡因成瘾的贡献。

关于可卡因的数十年研究已经产生了大量数据,这些数据回答了有关这种高度成瘾性药物性质的许多重要问题。可悲的是,这些信息都没有转化为治疗可卡因成瘾的有效疗法。这篇综述致力于评估可卡因研究的当前状态,以试图寻找治疗发展的新途径。例如,可卡因成瘾的风险是高度可遗传的,但是将可卡因依赖的个体与对照进行比较的全基因组分析并未产生有希望的药物开发目标。是因为成瘾的遗传学太复杂还是因为现有的研究方法不足?同样地,动物研究显示,长期暴露于可卡因后,基因表达发生了数十种持久变化,这些变化均未转化为治疗药物,因为所得化合物无效或产生了无法忍受的副作用。最近,注意力集中在由于反复摄入可卡因而引起的表观遗传修饰上,其中一些似乎可通过种系的改变而遗传。虽然表观遗传学的变化代表了治疗发展的新前景,但表观遗传学标记的选择性操作目前甚至在动物中也具有挑战性,因此翻译潜力是遥遥无期的前景。这项审查将揭示,尽管在了解可卡因成瘾的分子和生理基础方面取得了巨大进展,但仍有许多地方是个谜。
更新日期:2018-02-06
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