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）是基于大脑残疾的确定原因，尽管暴露于其他药物，即多余的使用，可能会加剧广告PAE相关的婴儿的结果。同时酒精和大麻素（SAC）的实践，即共同摄入是青少年和育儿年龄的成年人的新兴趋势。囊是由于酒精和大麻素放大器的联合使用而成熟和维护药物的心理效果。大麻素是致病性的已知贡献者。但是，我们几乎不知道SAC对出生结果的潜在后果。拟议研究的前提由已发表的文献告知，这表明 PAE效应部分是由大麻素受体信号通路的激活和 PAE和产前大麻素会产生类似的胎儿发育结果。而且，最近发表的数据显示了亚周期性剂量之间的发展协同作用非哺乳动物脊椎动物模型中的大麻素和乙醇。基于这些我们计划解决两个问题：首先，“ SAC对胎儿更具破坏性开发比仅酒精或大麻素？”；其次，重要的是，“将大麻素拮抗剂可以防止Pae＆Sac的影响？”我们的研究将重点放在 SAC对神经发生和血管发生的影响，脉管系统的完整生长这支持胎儿脑的生长。我们计划将体内和离体小鼠PAE模型与分子测定和多动症和条件地位偏好的行为分析以及最先进的光学成像（光学相干断层扫描和灯页显微镜）和高分辨率超声成像，评估囊的影响（目标＃1）大脑和行为，以及（AIM＃2）关于血管生成和脑血管血流。我们的总体目标，以确定和最大程度地减少因素的贡献，包括多药的使用，这导致因PAE引起的脑疾病风险增加，与目标的目标一致 NIH（CRAN）倡议的成瘾合作研究。娱乐的迅速传播大麻使用意味着SAC是一种重要的新兴药物消费方式，并且对PAE效应严重程度的潜在贡献者。作为这些研究的结果，我们将获得证据来指导人类有关SAC出生结果的研究，并评估针对大麻素受体的新型药理干预策略作为一种手段预防PAE的或反向影响。