Maternally Transmitted Opiate Abuse Vulnerability

母婴传播阿片类药物滥用的脆弱性

• 批准号: 7729779
• 负责人: ELIZABETH M BYRNES
• 金额: $ 28.88万
• 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 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729779
• 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; 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; public health relevance; 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，药物滥用的遗传性是由遗传和环境因素造成的。最近的研究结果表明，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。表观遗传学一词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到子细胞或从亲本传递到子代，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传到下一代，但这些效应传递所涉及的机制尚不完全清楚。最近的一些研究结果表明，产前和产后的母体环境可能在表观遗传转移中发挥关键作用。迄今为止，表观遗传学在药物滥用家族模式中的作用尚未得到充分研究。过去十年中，青春期女性使用处方麻醉品的数量急剧增加。我们开发了雌性大鼠青春期吗啡暴露的动物模型，以检查在这个独特的发育时期使用阿片类药物的长期后果。我们的研究结果表明，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着变化外，青少年暴露于吗啡的雌性大鼠的后代也表现出对吗啡的反应性增强。这些后代效应表明青少年接触吗啡会增加下一代药物滥用的风险。该模型的一个重要方面是，暴露于吗啡的青春期雌性在交配前至少 10 天不吸毒。因此，发育中的后代永远不会直接接触吗啡。这意味着在后代中观察到的任何影响都是母源性的。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及其后代的长期影响中的作用。目前的提案将确定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）。它还将检查母体环境可能发生的变化，这些变化可能在这些后代效应的传播中发挥作用（具体目标 2）。最后，我们将测试产后处理是否可以改善或预防青少年吗啡暴露的跨代影响（具体目标 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青春期接触麻醉品的母亲如何增加其未来后代滥用药物的可能性。这些研究将为了解母亲因素在家庭药物滥用模式中的作用奠定基础。