Prenatal alcohol/cannabinoid co-exposures and fetal brain development

产前酒精暴露（PAE）是一个确定的原因，脑为基础的残疾，虽然共同的， 暴露于其他药物，即，多种物质的使用，可加重不良PAE相关 婴儿的结果。同时使用酒精和大麻（SAC）的做法，即，共 在青少年和育龄成年人中，这是一种新的趋势。囊 动机和维持，因为酒精和大麻素的结合使用放大了每一个 药物的心理作用。大麻素是已知的致畸性因素。但我们 我几乎不知道SAC对出生结果的潜在影响。 已发表的文献为拟议研究的前提提供了信息，这些文献表明， PAE效应部分由大麻素受体信号通路的激活介导， PAE和产前大麻素产生类似的胎儿发育结果。此外，委员会认为， 最近公布的数据显示，亚致畸剂量的 大麻素和乙醇在非哺乳类脊椎动物模型中的作用。基于这些，以及我们的 根据我们的初步数据，我们计划解决两个问题：第一，“SAC对胎儿的伤害更大吗？ 比单独使用酒精或大麻素更有效？"第二，也是最重要的，“将 大麻素拮抗剂保护免受PAE和SAC？的影响。我们的研究将集中在 SAC对神经发生和血管发生的影响， 支持胎儿大脑发育的细胞 我们计划使用体内和离体小鼠PAE模型结合分子测定， 多动和条件性位置偏爱的行为分析，以及最先进的 光学成像（光学相干断层扫描和光片显微镜）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。 我们的总体目标是确定并尽量减少各种因素的影响，包括多种药物的使用， 导致PAE导致脑残疾风险增加的因素，与 美国国立卫生研究院成瘾合作研究（CRAN）。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， PAE效应严重程度的潜在促成因素。作为这些研究的结果，我们将 获取证据，以指导SAC出生结果的人类研究，并评估 靶向大麻素受体的新型药理学干预策略， 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.