Maternally Transmitted Opiate Abuse Vulnerability

描述(由申请人提供)：许多研究表明，药物滥用的遗传性质是由遗传和环境因素造成的。最近的发现表明，调控基因和环境之间相互作用的一种机制是表观遗传修饰。表观遗传学是指DNA和组蛋白修饰，它调节基因的表达，并从母细胞传递给子细胞或从父母传递给后代，但不改变潜在的DNA序列。虽然很明显，表观遗传修饰可以从一代传到下一代，但这些效应的传递所涉及的机制还不完全清楚。最近的一些发现表明，母体环境，无论是出生前还是出生后，可能在表观遗传转移中发挥关键作用。到目前为止，表观遗传学在药物滥用家族模式中的作用还没有得到很好的研究。在过去十年中，青春期女性的处方麻醉剂使用量大幅增加。我们在雌性大鼠身上建立了青春期吗啡暴露的动物模型，以检验在这一独特的发育期使用鸦片类药物的长期后果。我们的发现表明，除了在青春期暴露于吗啡的成年雌性大鼠的基因表达发生显著变化外，暴露于青春期的雌性大鼠的后代对吗啡的反应增强。这些后代效应表明，青少年接触吗啡会增加下一代滥用药物的风险。这个模型的一个重要方面是，接触吗啡的青春期女性在交配前至少10天不吸毒。因此，发育中的后代永远不会直接接触吗啡。这意味着在后代身上观察到的任何影响都是母性的。本提案的目的是确定表观遗传学在青春期吗啡暴露对雌性及其后代的长期影响中的作用。目前的提案将确定在青少年发育期间接触吗啡的雌性成年后代的跨代表观遗传修饰(具体目标1)。它还将审查母体环境的可能变化，这些变化可能在这些后代影响的传递中发挥作用(具体目标2)。最后，我们将测试出生后手法是否可以改善或防止青少年接触吗啡的跨代影响(具体目标3)。了解药物引起的吗啡敏感性变化如何代代相传，将有助于确定药物滥用家族模式的基本机制以及可能的干预措施。公共卫生相关性：该项目的目标是了解在青春期接触毒品的母亲如何增加其未来子女滥用药物的可能性。这些研究将为理解母亲因素在药物滥用家庭模式中的作用提供基础。

DESCRIPTION (provided by applicant): Many studies have demonstrated that the hereditary nature of drug abuse is due to both genetic and environmental factors. Recent findings demonstrate that one mechanism regulating interactions between genes and the environment are epigenetic modifications. The term epigenetics refers to DNA and histone protein modifications that regulate gene expression and which are transmitted from a mother cell to a daughter cell or from a parent to a progeny, but which do not change the underlying DNA sequence. While it is clear that epigenetic modifications can be passed from one generation to the next, the mechanisms involved in the transmission of these effects are not fully understood. Several recent findings indicate that the maternal environment, both pre- and postnatal, may play a critical role in epigenetic transfer. To date, the role of epigenetics in familial patterns of drug abuse has not been well studied. Prescription narcotics use by adolescent females has increased dramatically in the past decade. We have developed an animal model of adolescent morphine exposure in female rats to examine the long-term consequences of opiate use during this unique developmental period. Our findings demonstrate that in addition to significant alterations in gene expression in adult female rats exposed to morphine during adolescence, the offspring of adolescent-exposed females demonstrate enhanced responsiveness to morphine. These offspring effects suggest adolescent morphine exposure increases the risk of drug abuse in the next generation. One of important aspect of this model is that adolescent morphine-exposed females are drug-free for at least 10 days prior to mating. Thus, developing offspring are never directly exposed to morphine. This means that any effect observed in the offspring is maternally-derived. The purpose of the present proposal is to determine the role of epigenetics in the long-term effects of adolescent morphine exposure on both the female and her offspring. The current proposal will identify transgenerational epigenetic modifications in the adult offspring of females exposed to morphine during adolescent development (Specific Aim 1). It will also examine possible changes in the maternal environment which may play a role in the transmission of these offspring effects (Specific Aim 2). Finally, we will test whether postnatal manipulations can ameliorate or prevent the transgenerational effects of adolescent morphine exposure (Specific Aim 3). Understanding how drug-induced alterations in morphine sensitivity may be passed from one generation to the next will help identify basic mechanisms underlying familial patterns of drug abuse as well as possible interventions. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand how mothers who are exposed to narcotics during adolescence increase the probability of drug abuse in their future offspring. These studies will provide a foundation for understanding the role of maternal factors in familial patterns of drug abuse.