Prenatal alcohol/cannabinoid co-exposures and fetal brain development

产前酒精暴露(PAE)是基于大脑的残疾的一个既定原因，尽管 暴露于其他药物，即多物质使用，可加剧与PAE相关的不良反应 婴儿结局。同时使用酒精和大麻素的做法，即联合 摄取，是青少年和育龄成年人中的一种新兴趋势。国资委是 激励和维持，因为酒精和大麻素的联合使用放大了每一个 毒品的心理效应。大麻类化合物是已知的致畸因素。然而，我们 对SAC对出生结局的潜在后果几乎一无所知。 拟议研究的前提是由已发表的文献提供信息，这表明 PAE的作用部分是通过激活大麻素受体信号通路和 PAE和产前大麻素会产生相似的胎儿发育结果。此外， 最近公布的数据显示，亚致畸剂量之间的发育协同作用 非哺乳动物脊椎动物模型中的大麻素和乙醇。基于这些，以及我们的 我们计划解决两个问题：第一，SAC对胎儿的伤害更大吗？ 比酒精或大麻素单独发育更好吗？“；第二，也是重要的，” 大麻素拮抗剂可防止PAE和SAC的影响？“我们的研究将集中在 SAC对神经发生和血管生成以及血管系统互补生长的影响 这有助于胎儿大脑的发育。 我们计划使用体内和体外的小鼠PAE模型，结合分子检测和 多动症和条件性位置偏好的行为分析，以及最新的 光学成像(光学相干层析成像和薄片显微镜)和高分辨率 超声成像，以评估SAC对(目标1)大脑和行为的影响，以及(目标2) 对血管生成和脑血管血流的影响。 我们的首要目标是确定和最大限度地减少包括多种药物使用在内的因素的影响， 导致由于PAE导致的大脑残疾风险增加，这与以下目标一致 美国国立卫生研究院关于成瘾的合作研究(CRAN)倡议。休闲娱乐的迅速普及 大麻的使用意味着SAC是一种重要的新兴毒品消费模式，而 PAE效应严重程度的潜在贡献者。作为这些研究的结果，我们将 获取证据以指导人类对SAC出生结局的研究，并评估 针对大麻素受体的新的药物干预策略作为一种手段 预防或逆转PAE的影响。

Prenatal alcohol exposure (PAE) is an established cause of brain-based disability, though co- exposure to other drugs, i.e., poly-substance use, can exacerbate adverse PAE-associated infant outcomes. The practice of Simultaneous Alcohol and Cannabinoid (SAC) use, i.e., co- ingestion, is an emerging trend among adolescents and adults of child-bearing age. SAC is motivated and maintained because combined use of alcohol and cannabinoids amplifies each drug’s psychological effect. Cannabinoids are known contributors to teratogenicity. However, we know virtually nothing about potential consequences of SAC for birth outcomes. The premise of the proposed studies is informed by the published literature, which indicates that PAE effects are, in part, mediated by activation of cannabinoid receptor signaling pathways and that PAE and prenatal cannabinoids engender similar fetal developmental outcomes. Moreover, recently published data shows developmental synergy between sub-teratogenic doses of cannabinoids and ethanol in non-mammalian vertebrate models. Based on these, as well as our own preliminary data we plan to address two questions: Firstly, “is SAC more damaging to fetal development than either alcohol or cannabinoids alone?”; Secondly, and importantly, “will cannabinoid antagonists protect against effects of PAE & SAC?”. Our studies will focus on the effects of SAC on neurogenesis and vasculogenesis, the complementary growth of vasculature that supports fetal brain growth. We plan to use in vivo and ex vivo mouse PAE models in combination with molecular assays and behavioral assays for hyperactivity and conditioned place preference, as well as state-of-the-art optical imaging (optical coherence tomography and light-sheet microscopy) and high-resolution ultrasound imaging, to assess the effects of SAC on, (Aim #1) brain and behavior, and (Aim #2) on vasculogenesis and cerebrovascular blood flow. Our overarching goal, to identify and minimize the contribution of factors, including poly-drug use, that contribute to increased risk for brain disabilities due to PAE, is consistent with the goals of the Collaborative Research on Addiction at NIH (CRAN) initiative. The rapid spread of recreational cannabis use means that SAC is an important emerging mode of drug consumption, and a potential contributor to the severity of PAE effects. As an outcome of these studies, we will acquire evidence to guide human studies on SAC birth outcomes, and to assess the efficacy of novel pharmacological intervention strategies targeted to cannabinoid receptors as a means to prevent or reverse effects of PAE.