Maternally Transmitted Opiate Abuse Vulnerability

母婴传播阿片类药物滥用的脆弱性

基本信息

批准号：
8577805
负责人：
ELIZABETH M BYRNES
金额：
$ 37.13万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8577805
关键词：
17 year old Adolescence Adolescent Adrenal Glands Adult Children Alcohol or Other Drugs use Analgesics Animal Model Animals Behavior Caring Cocaine Data Development Disease Dopamine Drug usage Endocrine Endocrine Disruptors Endocrine system Environment Environmental Risk Factor Etiology Exposure to Extinction (Psychology)Female Female Adolescents Future Future Generations Gene Expression Generations Goals Health Hormones Human Hypothalamic structure Intake Intergenerational transfer Maintenance Marijuana Medical Metabolism Modeling Modification Morphine Nature Nutritional status Opiates Opioid Overdose Oxycodone Partner in relationship Pattern Perinatal Exposure Pharmaceutical Preparations Phenotype Pituitary Gland Play Population Prevalence Public Health Rattus Regulation Reinforcement Schedule Reporting Rewards Risk Role Self Administration Sexual Maturation Stress Substance Use Disorder Substance abuse problem System Testing Variant Vicodin Work addiction adolescent drug use base critical period dopamine system drug of abuse drug seeking behavior endogenous opioids environmental enrichment for laboratory animals environmental stressor hypothalamic-pituitary-adrenal axis insight intergenerational male next generation non-genomic offspring opioid abuse prescription opiate public health relevance relating to nervous system reproductive reproductive axis reproductive function research study reward circuitry sex transmission process

项目摘要

DESCRIPTION (provided by applicant): Prescription opiate use by adolescent females has increased dramatically in the past decade. This use is highly problematic, not only due to the risks of overdose and addiction, but also due to the potential neurodevelopmental effects these drugs may have during this sensitive period. In female populations, such developmental use may also significantly impact the reproductive axis given the role that endogenous opioids play in both sexual maturation and reproductive function. By altering neural and endocrine development, short-term opiate use during adolescence could trigger long-term modifications in the female, which are then transmitted to her future offspring even in the absence of continued use. Over the past few years, 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. These studies revealed significant modifications in both gene expression and behavior in the offspring (F1 generation) of morphine exposed females. These transgenerational effects occur in the absence of in utero exposure, as all of the adolescent morphine-exposed females are drug-free for at least 21 days prior to mating. Moreover, we have recently extended our observations to the F2 generation and continue to observe effects. The nature of these modifications suggests a phenotype that may be more vulnerable to substance abuse. Interestingly, many of these effects are sex-specific. The purpose of the present proposal is to characterize the abuse potential of this phenotype using drug self-administration. Thus, we aim to characterize morphine self-administration behavior including acquisition, maintenance and reinstatement (Specific Aim 1); and compare it to cocaine self-administration acquisition, maintenance, and reinstatement (Specific Aim 2). Finally, we aim to examine the impact of both environmental enrichment and stress on the expression of this phenotype (Specific Aim 3). Studies will determine the persistence of offspring effects in the F2 generation and, by examining both male and female offspring, will also determine whether observed transgenerational effects are sexually dimorphic. Moreover, by examining two distinct drugs of abuse, we can delineate differential patterns within the reward circuitry that will provid insight into the mechanism of action of the observed phenotype. Given the increased use of opiates in this population (both medical and non-medical), understanding the persistent developmental effects of these drugs will delineate potential risks associated with opiate use beyond the direct effects on the user. We view this work in the context of intergenerational, non-genomic transfer of substance use disorders.

描述（由申请人提供）：过去十年中，青春期女性处方阿片类药物的使用急剧增加。这种使用存在很大的问题，不仅因为服用过量和成瘾的风险，还因为这些药物在这个敏感时期可能产生潜在的神经发育影响。在女性群体中，考虑到内源性阿片类药物在性成熟和生殖功能中发挥的作用，这种发育用途也可能显着影响生殖轴。通过改变神经和内分泌发育，青春期短期使用阿片类药物可能会引发女性的长期改变，即使没有继续使用，这种改变也会遗传给她未来的后代。在过去的几年中，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。这些研究揭示了吗啡暴露雌性的后代（F1 代）的基因表达和行为发生了显着变化。这些跨代效应是在没有宫内暴露的情况下发生的，因为所有暴露于吗啡的青少年雌性在交配前至少 21 天都没有吸毒。此外，我们最近将观察范围扩大到了F2代，并继续观察效果。这些修饰的性质表明表型可能更容易受到药物滥用的影响。有趣的是，其中许多影响是具有性别特异性的。本提案的目的是通过自我给药来表征这种表型的滥用潜力。因此，我们的目标是描述吗啡自我给药行为，包括获取、维持和恢复（具体目标 1）；并将其与可卡因自我给药获取、维持和恢复进行比较（具体目标 2）。最后，我们的目标是研究环境富集和胁迫对该表型表达的影响（具体目标 3）。研究将确定 F2 代中后代效应的持续性，并通过检查雄性和雌性后代，还将确定观察到的跨代效应是否具有性别二态性。此外，通过检查两种不同的滥用药物，我们可以描绘奖励回路内的差异模式，这将有助于深入了解观察到的表型的作用机制。鉴于阿片类药物在该人群中的使用量不断增加（包括医疗和非医疗），了解这些药物对发育的持续影响将描述与阿片类药物使用相关的潜在风险，而不仅仅是对使用者的直接影响。我们在物质使用障碍的代际、非基因组转移的背景下看待这项工作。