Maternally Transmitted Opiate Abuse Vulnerability

母婴传播阿片类药物滥用的脆弱性

• 批准号: 8033830
• 负责人: ELIZABETH M BYRNES
• 金额: $ 27.73万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033830
• 关键词: Adolescence; Adolescent; Adolescent Development; Adult; Adult Children; Alcohols; Animal Model; Brain region; Cells; Characteristics; Child; Complex; Corpus striatum structure; DNA; DNA Sequence; Data; Daughter; Dependence; Development; Dorsal; Dose; Drug Exposure; Drug abuse; Environment; Environmental Risk Factor; Epigenetic Process; Exposure to; Family; Female; Female Adolescents; Fertility; Fostering; Foundations; Future; Gene Expression; Generations; Genes; Genetic; Goals; Growth; Health; Histone Acetylation; Histone Deacetylase Inhibitor; Histones; Home environment; Human; Hypothalamic structure; Inherited; Intervention; Lactation; Life; Long-Term Effects; Maternal Behavior; Measures; Modeling; Modification; Morphine; Mothers; Motivation; Narcotics; Nature; Opiates; Opioid Receptor; Parents; Partner in relationship; Pattern; Pharmaceutical Preparations; Play; Population; Post-Translational Protein Processing; Postpartum Period; Probability; Promoter Regions; Rattus; Regulation; Relative (related person); Reproductive Behavior; Rewards; Risk; Risk Factors; Role; Running; Saline; Sexual Maturation; Structure of nucleus infundibularis hypothalami; Substance abuse problem; System; Testing; Vagina; Work; base; daughter cell; design; drug of abuse; endogenous opioids; genome-wide; mRNA Expression; male; neuroadaptation; neuroregulation; next generation; offspring; opioid abuse; peripubertal period; postnatal; preference; prenatal; prevent; pup; reproductive; research study; response; transmission process

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.

描述（由申请人提供）：许多研究表明，滥用药物的遗传性质是由于遗传和环境因素引起的。最近的发现表明，调节基因与环境之间相互作用的一种机制是表观遗传修饰。术语表观遗传学是指调节基因表达并从母细胞传播到子细胞或从父母到后代的DNA和组蛋白蛋白修饰，但不会改变潜在的DNA序列。虽然很明显，表观遗传修饰可以从一代人传递到第二代，但涉及这些效果传播的机制尚未完全了解。最近的一些发现表明，出生前和产后的孕产妇环境可能在表观遗传转移中起关键作用。迄今为止，表观遗传学在药物滥用的家族模式中的作用尚未得到很好的研究。在过去的十年中，青少年女性使用处方麻醉品的使用急剧增加。我们已经开发了女性大鼠青春期吗啡暴露的动物模型，以检查这个独特的发育时期鸦片使用的长期后果。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中基因表达的显着改变外，青少年暴露的女性的后代还表现出对吗啡的反应性增强。这些后代效应表明，青春期吗啡的暴露会增加下一代药物滥用的风险。该模型的重要方面之一是，青少年裸露的女性在交配前至少10天无药物。因此，发展后代永远不会直接暴露于吗啡。这意味着在后代中观察到的任何效果都是母体衍生的。本提案的目的是确定表观遗传学在青少年吗啡暴露对女性和她后代的长期影响中的作用。当前的建议将确定在青少年发育期间暴露于吗啡的成年女性后代的转世表观遗传学修饰（特定目标1）。它还将检查孕产妇环境中可能的变化，这些变化可能在这些后代效应的传播中发挥作用（特定目标2）。最后，我们将测试产后操纵是否可以改善或防止青少年吗啡暴露的转世代作用（特定目标3）。了解药物诱导的吗啡敏感性的改变可能会从一代人传递到第二代，将有助于确定药物滥用的家族模式以及可能的干预措施的基本机制。公共卫生相关性：该项目的目的是了解青春期暴露于麻醉品的母亲如何增加未来后代药物滥用的可能性。这些研究将为了解母体因素在药物滥用的家族模式中的作用提供基础。