Nash Family Department of Neuroscience, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
Nash Family Department of Neuroscience, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
Curr Opin Neurobiol. 2019 Dec;59:128-136. doi: 10.1016/j.conb.2019.05.005. Epub 2019 Jun 27.
As an individual becomes addicted to a drug of abuse, nerve cells within the brain's reward circuitry adapt at the epigenetic level during the course of repeated drug exposure. These drug-induced epigenetic adaptations mediate enduring changes in brain function which contribute to life-long, drug-related behavioral abnormalities that define addiction. Targeting these epigenetic alterations will enhance our understanding of the biological basis of addiction and might even yield more effective anti-addiction therapies. However, the complexity of the neuroepigenetic landscape makes it difficult to determine which drug-induced epigenetic changes causally contribute to the pathogenic mechanisms of drug addiction. In this review, we highlight the evidence that epigenetic modifications, specifically histone modifications, within key brain reward regions are correlated with addiction. We then discuss the emerging field of locus-specific neuroepigenetic editing, which is a promising method for determining the causal epigenetic molecular mechanisms that drive an addicted state. Such approaches will substantially increase the field's ability to establish the precise epigenetic mechanisms underlying drug addiction, and could lead to novel treatments for addictive disorders.
随着个体对滥用药物成瘾,在反复药物暴露过程中,大脑奖励回路中的神经细胞会在表观遗传水平上发生适应性改变。这些药物引起的表观遗传适应性改变介导了大脑功能的持久变化,导致了终身的、与药物相关的行为异常,从而定义了成瘾。针对这些表观遗传改变将增强我们对成瘾生物学基础的理解,甚至可能产生更有效的抗成瘾治疗方法。然而,神经表观遗传学景观的复杂性使得很难确定哪些药物引起的表观遗传变化因果上有助于药物成瘾的发病机制。在这篇综述中,我们强调了证据,即关键大脑奖励区域内的表观遗传修饰(特别是组蛋白修饰)与成瘾有关。然后,我们讨论了新兴的特定基因座神经表观遗传编辑领域,这是一种确定驱动成瘾状态的因果表观遗传分子机制的有前途的方法。这种方法将极大地提高该领域确定药物成瘾背后的精确表观遗传机制的能力,并可能为成瘾障碍带来新的治疗方法。