Substance abuse: Individual differences in behavior and epigenetics

描述(申请人提供)：海洛因成瘾是一种慢性复发性疾病，通过贬低个人责任和有利于寻找和使用毒品的关系来损害个人。海洛因尤其令人不安，因为它最近在美国的使用量上升，而且一项新的研究将海洛因标记为对吸毒者和社会第二危险的毒品[1]。考虑到海洛因使用的不良后果，戒毒的目标对吸毒者来说非常重要。不幸的是，复发率相当高。因此，问题就产生了：为什么每个人的复发结果都不同？许多报告表明，环境因素和遗传因素之间存在很大的相互作用，这些因素导致复发结果的变异性。因此，目前的建议将研究个体差异如何在特定目标1的多个时间段内影响复发结果。我们的实验室在通过检测动物对药物的自然奖励线索的贬值程度来追踪个体对药物滥用敏感性的差异方面拥有相当多的经验。极大地避免药物与自然奖励配对的啮齿动物表现出更强的工作和吸毒动机[2，3]。与海洛因配对的球杆也是如此。表观遗传差异可能导致对药物反应的个体差异[4]，特别是DNA甲基化，鉴于其感知的稳定性，已被视为复发的潜在因素。然而，目前的DNA甲基化研究只是触及了皮毛。据我们所知，还没有研究检查对海洛因反应不同的大鼠的DNA甲基化差异，或确定这些变化是否真的是戒毒期间的永久性变化。然后，特定目标3将使用特定目标1中的大鼠来确定对海洛因的不同反应是否与大脑中DNA甲基化的差异有关。最后，学习和记忆领域已经表明，环境丰富可以改变表观遗传环境，我们的数据[5]和其他人的数据[6-9]表明，丰富可以防止成瘾行为。因此，下一步是确定浓缩状态是否不仅可以保护大鼠免受药物诱导的恢复(特定目标2)，而且还可以保护伴随的表观遗传学变化。特定目标3将使用特定目标2中的大鼠的大脑来解决这个问题。在与弗里曼实验室的合作下，我们最近开发了一种新的下一代测序方法来进行座位特异性DNA甲基化分析，并获得了试点数据，将海洛因的反应增强与明显的海马区DNA甲基化长寿联系起来。从这一知识差距中，我试图了解一个人对海洛因的反应如何影响戒酒和复发，并将这些个体在脆弱性方面的差异与DNA甲基化联系起来。

DESCRIPTION (provided by applicant): Heroin addiction is a disease of chronic relapse that harms the individual through devaluation of personal duties and relationships in favor of finding and using drugs. Heroin in particular is disconcerting given its recent rise of use in the United States, and a new study labeling heroin the second most dangerous drug to the user and society [1]. Given the adverse consequences of heroin use, the goal to be drug free holds great importance for the user. Unfortunately, the incidence of relapse is quite high. Thus the question arises: Why do individuals have different relapse outcomes? A number of reports have shown a large interplay between environmental and genetic factors that contribute to the variability in relapse outcomes. Therefore the current proposal will examine how individual differences affect relapse outcome across multiple time periods in Specific Aim 1. Our laboratory has considerable experience in tracking individual differences in sensitivity to drugs of abuse by examining to what extent an animal devalues a drug paired natural reward cue. Rodents that greatly avoid a drug paired natural reward cue display increased motivation to work and take drug [2, 3]. This is the case for a heroin-paired cue as well. Epigenetic differences may contribute to such individual differences in response to drug [4], and DNA methylation, in particular, has been examined as potential factor for relapse given its perceived stability. Nevertheless, current DNA methylation studies have only scratched the surface. No studies, to our knowledge, have examined the DNA methylation differences in rats that respond differently to heroin or determined whether these changes are truly permanent during abstinence. Specific Aim 3, then, will use the rats from Specific Aim 1 to determine whether differential responding to heroin is linked to differences in DNA methylation in brain. Finally, the learning and memory field has shown that environmental enrichment can alter the epigenetic the landscape and our data [5], and those of others [6-9], have shown that enrichment can protect against addiction-like behaviors. Therefore, a next step is to determine if enrichment status can protect a rat from not only drug-induced reinstatement (Specific Aim 2), but also the accompanying epigenetic changes. Specific Aim 3 will use the brains from rats from Specific Aim 2 to address this question. In collaboration with the Freeman laboratory, we recently developed a novel next generation sequencing approach to loci-specific DNA methylation analysis and obtained pilot data linking increased responsiveness to heroin in the model with a distinct hippocampal DNA methylation prolife. From this gap in knowledge, I seek to understand how an individual's response to heroin affects abstinence and relapse and link these individual differences in vulnerability with DNA methylation.