Sex Differences in Adolescent Exposure to Morphine on Reward Related Behaviors in Subsequent Offspring

描述（由申请人提供）：在过去十年中，青少年女性处方阿片类药物的使用急剧增加。这种使用是非常有问题的，不仅因为过量和成瘾的风险，而且还因为这些药物在这个敏感时期可能对神经发育产生潜在的影响。在女性人群中，鉴于内源性阿片类药物在性成熟和生殖功能中所起的作用，这种发育性使用也可能显著影响生殖轴。通过改变神经和内分泌发育，在青春期短期使用阿片类药物可能会引发雌性的长期变化，即使没有继续使用，这些变化也会遗传给她未来的后代。在过去的几年里，我们开发了一种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阿片类药物使用的长期后果。这些研究揭示了吗啡暴露雌性小鼠后代（F1代）基因表达和行为的显著改变。这些跨代效应发生在没有子宫暴露的情况下，因为所有暴露于吗啡的青春期雌性在交配前至少21天没有吸毒。此外，我们最近将我们的观察扩展到F2代，并继续观察效应。这些修饰的性质表明，一种表型可能更容易受到药物滥用的影响。有趣的是，许多这些影响是性别特异性的。本建议的目的是利用药物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（Specific aim 1）；并将其与可卡因自我给药的获得、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应激对该表型表达的影响（Specific aim 3）。研究将确定后代效应在F2代的持久性，并且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两性二态性。此外，通过检查两种不同的滥用药物，我们可以描绘奖赏回路中的不同模式，这将为观察到的表型的作用机制提供见解。鉴于这一人群中阿片类药物的使用（包括医疗和非医疗）有所增加，了解这些药物对发育的持续影响将描绘出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。

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.