Maternally Transmitted Opiate Abuse Vulnerability

描述(申请人提供)：在过去十年中，青春期女性处方阿片类药物的使用量急剧增加。这种使用是非常有问题的，不仅是因为服药过量和成瘾的风险，还因为这些药物在这一敏感时期可能会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的作用，这种发育用途也可能显著影响生殖轴。通过改变神经和内分泌发育，青春期短期服用阿片类药物可能会在雌性体内引发长期的改变，然后即使在没有继续使用的情况下，这些改变也会传递给未来的后代。在过去的几年里，我们在雌性大鼠身上建立了一个青春期吗啡暴露的动物模型，以检验在这一独特的发育时期使用阿片类药物的长期后果。这些研究表明，在接触吗啡的雌性小鼠的后代(F1代)中，基因表达和行为都发生了显著的变化。这些跨代影响发生在没有宫内接触的情况下，因为所有接触吗啡的青春期女性在交配前至少21天不使用药物。此外，我们最近将我们的观察扩展到F2代，并继续观察效果。这些修饰的性质表明，这种表型可能更容易受到药物滥用的影响。有趣的是，这些影响中的许多都是性别特有的。本提案的目的是利用药物自我给药来表征这一表型的滥用潜力。因此，我们的目标是刻画吗啡自我给药行为的特征，包括获得、维持和恢复(特定目标1)；并将其与可卡因自我给药获得、维持和恢复(特定目标2)进行比较。最后，我们的目标是研究环境丰富和胁迫对这一表型表达的影响(特定目标3)。研究将确定后代效应在F2代中的持久性，并通过检查男性和女性后代，也将确定观察到的跨代影响是否具有性别二型性。此外，通过研究两种不同的滥用药物，我们可以描绘出奖励回路中的不同模式，这将为观察到的表型的作用机制提供洞察。鉴于阿片剂在这一人群中的使用增加(医疗和非医疗)，了解这些药物的持久发展影响将勾勒出除对使用者的直接影响之外与阿片类药物使用有关的潜在风险。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。

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.