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Prenatal alcohol/cannabinoid co-exposures and fetal brain development

产前酒精/大麻素共同暴露与胎儿大脑发育

基本信息

批准号：
10827625
负责人：
Kirill V Larin
金额：
$ 5.83万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10827625
关键词：
3-Dimensional Acute Address Adolescent Adult Age Alcohol consumption Alcohols Anatomy Angiogenesis Inhibition Behavior Behavioral Behavioral Assay Biological Assay Birth Blood Vessels Blood flow Brain Cannabinoids Cells Cerebrovascular Circulation Consumption Data Defect Development Developmental Disabilities Dose Drug usage Ethanol Exposure to Fetal Alcohol Exposure Fetal Development Fetal alcohol effects Fetus Goals Growth Histologic Human Hyperactivity Impairment Ingestion Intervention Intoxication Label Legal Light Literature Maternal Exposure Mediating Microscopy Modeling Molecular Molecular Analysis Mus Neurodevelopmental Disability Optical Coherence Tomography Outcome Outcome Study Pharmaceutical Preparations Placenta Positioning Attribute Pregnancy Outcome Public Policy Publishing Receptor Activation Recreation Reporter Reporting Research Resolution Risk Risk Taking Rodent Second Pregnancy Trimester Severities Signal Pathway Signal Transduction Teratogens Testing Ultrasonography United States National Institutes of Health Zebrafish addiction alcohol exposure angiogenesis behavioral outcome blood vessel development brain based brain size cannabinoid receptor cannabinoid receptor antagonist child bearing conditioned place preference craniofacial disability efficacy evaluation fetal in vivo indexing infant outcome innovation malformation marijuana legalization marijuana use mouse model multiple drug use nerve stem cell neural neurogenesis neurovascular novel offspring optical imaging pharmacologic polysubstance use preference prenatal prevent protective effect psychologic synergism synthetic cannabinoid trend vasculogenesis virtual young adult

项目摘要

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.

产前酒精暴露（PAE）是导致大脑残疾的一个确定原因，尽管接触其他药物，即使用多种物质，可能会加剧与 PAE 相关的不良反应婴儿结局。同时使用酒精和大麻素（SAC）的做法，即共同使用摄入，是青少年和育龄成人中的一个新兴趋势。 SAC 是受到激励和维持，因为酒精和大麻素的结合使用会放大每种物质药物的心理作用。大麻素是已知的致畸因素。然而，我们对 SAC 对出生结果的潜在影响几乎一无所知。拟议研究的前提是基于已发表的文献，这表明 PAE 效应部分是由大麻素受体信号通路的激活介导的 PAE 和产前大麻素会产生相似的胎儿发育结果。而且，最近发表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对胎儿的损害更大吗？” 比单独使用酒精或大麻素更能促进发展吗？”；其次，也是重要的，“将大麻素拮抗剂可以防止 PAE 和 SAC 的影响吗？”。我们的研究将集中于 SAC 对神经发生和血管发生、脉管系统的互补生长的影响支持胎儿大脑发育。我们计划将体内和离体小鼠 PAE 模型与分子测定相结合，针对多动症和条件性位置偏好的行为测定，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，评估 SAC 对（目标 #1）大脑和行为的影响，以及（目标 #2）对血管发生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 导致脑部残疾的风险增加，与 NIH 成瘾合作研究 (CRAN) 倡议。休闲娱乐的迅速普及大麻使用意味着 SAC 是一种重要的新兴毒品消费模式， PAE 影响严重程度的潜在因素。作为这些研究的结果，我们将获取证据来指导 SAC 出生结果的人类研究，并评估 SAC 的有效性针对大麻素受体的新型药理干预策略预防或逆转 PAE 的影响。