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

• 批准号: 10616046
• 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
• 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/10616046
• 关键词: 3-Dimensional; Acute; Address; Adolescent; Adult; Age; Alcohol consumption; Alcohols; Anatomy; Base of the Brain; 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; Pharmacology; Placenta; Positioning Attribute; Pregnancy Outcome; Public Policy; Publishing; Receptor Activation; Reporter; 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; base; behavioral outcome; blood vessel development; brain behavior; brain size; cannabinoid receptor; cannabinoid receptor antagonist; child bearing; conditioned place preference; craniofacial; disability; fetal; in vivo; indexing; infant outcome; innovation; malformation; marijuana legalization; marijuana use; mouse model; multiple drug use; nerve stem cell; neurogenesis; neurovascular; novel; offspring; optical imaging; polysubstance use; preference; prenatal; prevent; protective effect; psychologic; relating to nervous system; synergism; synthetic cannabinoid; trend; vasculogenesis; virtual; young adult

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 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。 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 大麻素是已知的致畸因素。 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 和产前大麻素的性别与胎儿发育结果相似。 最近发表的数据显示亚致畸剂量之间的发育协同作用 基于这些以及我们的非哺乳动物脊椎动物模型中的大麻素和乙醇。 有了初步数据，我们计划解决两个问题：第一，“SAC对胎儿的伤害更大吗？” 其次，重要的是，“会比单独使用酒精或大麻素更有效吗？” 大麻素拮抗剂可以防止 PAE 和 SAC 的影响吗？”。 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，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 美国国立卫生研究院 (NIH) 成瘾合作研究 (CRAN) 倡议 娱乐活动的迅速传播。 大麻使用意味着 SAC 是一种重要的新兴毒品消费模式， 作为这些研究的结果，我们将确定 PAE 影响严重程度的潜在因素。 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。