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

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

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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）：在过去的十年中，青少年女性的处方鸦片使用量显着增加。这种用途是高度问题的，不仅是由于过量和成瘾的风险，而且还因为这些药物在这个敏感时期可能具有的潜在神经发育作用。在女性人群中，考虑到内源性阿片类药物在性成熟和生殖功能中的作用，这种发育使用也可能会显着影响生殖轴。通过改变神经和内分泌的发育，青春期的短期鸦片使用可能会触发女性的长期修饰，即使在没有继续使用的情况下，这些女性即使在未来的后代也会传播到她的未来后代。在过去的几年中，我们开发了一种在雌性大鼠中的青少年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。这些研究揭示了吗啡暴露的女性的后代（F1产生）中基因表达和行为的显着修饰。这些跨代作用发生在不存在子宫内的情况下，因为所有青少年暴露于吗啡的女性在交配前至少21天都没有药物。此外，我们最近将观察结果扩展到了F2的一代，并继续观察效果。这些修饰的性质表明一种表型可能更容易受到滥用药物的影响。有趣的是，其中许多效果都是针对性的。本提案的目的是使用药物自我管理来表征这种表型的滥用潜力。因此，我们旨在表征吗啡自我管理行为，包括获取，维护和恢复原状（特定目标1）；并将其与可卡因自我管理，维护和恢复原状（特定目的2）进行比较。最后，我们旨在研究环境富集和压力对这种表型表达的影响（特定目的3）。研究将确定F2一代中后代效应的持久性，并通过检查男性和女性后代，还将确定观察到的转世效应是否是性二态性的。此外，通过检查两种不同的滥用药物，我们可以在奖励电路中描述差异模式，以提供对观察到的表型作用机理的见解。鉴于该人群中阿片类药物的使用越来越多（医学和非医学），了解这些药物的持续发育效果将描绘出与鸦片使用有关的潜在风险，而不是直接影响用户的影响。我们在代际，非基因组转移物质使用障碍的背景下查看这项工作。