Maternally Transmitted Opiate Abuse Vulnerability

描述（由申请人提供）：许多研究表明，药物滥用的遗传性是由遗传和环境因素共同造成的。最近的研究表明，调控基因与环境相互作用的一种机制是表观遗传修饰。表观遗传学是指调节基因表达的DNA和组蛋白修饰，这些修饰从母细胞传递给子细胞或从亲代传递给子代，但不改变潜在的DNA序列。虽然表观遗传修饰可以从一代传递到下一代是很清楚的，但这些影响传递的机制还没有完全了解。最近的一些研究结果表明，母体环境，无论是产前还是产后，都可能在表观遗传转移中发挥关键作用。迄今为止，表观遗传学在家族性药物滥用模式中的作用尚未得到很好的研究。在过去十年中，青少年女性使用处方麻醉品的人数急剧增加。我们开发了一种雌性大鼠青春期吗啡暴露的动物模型，以检查在这一独特的发育时期阿片类药物使用的长期后果。我们的研究结果表明，除了青春期暴露于吗啡的成年雌性大鼠的基因表达显著改变外，青春期暴露于吗啡的雌性大鼠的后代对吗啡的反应性增强。这些对后代的影响表明，青少年接触吗啡会增加下一代滥用药物的风险。该模型的一个重要方面是，青春期暴露于吗啡的雌性在交配前至少10天不吸毒。因此，发育中的后代从未直接接触过吗啡。这意味着在后代身上观察到的任何影响都是来自母亲。本研究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。目前的建议将确定在青春期发育期间暴露于吗啡的雌性成年后代的跨代表观遗传修饰（Specific Aim 1）。它还将研究可能在这些后代影响的传播中发挥作用的母亲环境的变化（具体目标2）。最后，我们将测试产后操作是否可以改善或防止青少年吗啡暴露的跨代效应（特定目标3）。了解药物引起的吗啡敏感性改变如何从一代传递到下一代，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麻醉品的母亲如何增加其后代滥用毒品的可能性。这些研究将为了解母亲因素在家族性药物滥用模式中的作用奠定基础。

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.