Role of the Endocannabinoid Signaling in Fetal Alcohol Spectrum Disorders

内源性大麻素信号传导在胎儿酒精谱系障碍中的作用

• 批准号: 8048839
• 负责人: VINOD K YARAGUDRI
• 金额: $ 21.2万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-05 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048839
• 关键词: Acetaldehyde; Acute; Address; Adolescence; Adolescent; Adult; Adult Children; Affect; Age; Alcohol abuse; Alcohol consumption; Alcohols; Amygdaloid structure; Attention; Attenuated; Behavior; Behavior Therapy; Behavioral; Birth; Brain; Brain region; CNR1 gene; Child; Clinical; Cognition; Congenital Heart Defects; Corpus striatum structure; Defect; Development; Dextrins; Disease; Dose; Drug Delivery Systems; Endocannabinoids; Ethanol; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; First Pregnancy Trimester; Functional disorder; Goals; Health; Hippocampus (Brain); Human; Intervention; Knowledge; Laboratories; Lead; Link; Lipids; Malnutrition; Maltose; Mediating; Membrane; Modeling; Molecular; Mus; Neuraxis; Neurites; Neurobiology; Neurons; Outcome; Pharmaceutical Preparations; Plastics; Play; Pregnancy; Prostaglandins; Puberty; Rattus; Research; Rewards; Risk-Taking; Rodent; Role; Signal Transduction; Social Problems; System; Therapeutic Intervention; Time; Toxic effect; adolescent offspring; alcohol behavior; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; base; craniofacial; critical period; dextrin; drinking behavior; drug of abuse; fetus hypoxia; frontal lobe; implantation; in utero; interest; male; migration; mouse model; nervous system development; neurochemistry; neuromechanism; neuropsychiatry; neurotrophic factor; offspring; pregnant; social; synaptogenesis; therapeutic target

DESCRIPTION (provided by applicant): Abuse of alcohol (ethanol) during pregnancy has been linked to a wide range of birth-related defects collectively known as Fetal Alcohol Spectrum Disorders (FASD), which are characterized by an array of developmental defects include craniofacial and cardiac malformations. Prenatal alcohol exposure also impairs the development of central nervous system (CNS) leading to several abnormal behaviors in the offspring including vulnerability to alcohol abuse. It remains a significant clinical challenge and an important social problem. Although interventions for specific outcomes are now emerging, there are currently no clinical therapies for the treatment of global fetal alcohol effects. In spite of some progress in delineating the mechanisms contributing to FASD, gaps in our knowledge still largely remain. The recently discovered endocannabinoid system has become a focus of intense research in understanding its significance in health and disease. There is accumulating evidence now implicating a role of the endocannabinoid system in several neuropsychiatric disorders including alcohol related behavior. Our preliminary studies indicate selective abnormalities in the components of endocannabinoid system in the striatum and a greater alcohol drinking behavior in utero alcohol exposed adolescent offspring mice. Based on these evidences and our preliminary findings, we hypothesize that alcohol exposure during critical periods of gestation adversely affects the endocannabinoid system, one among many other targets, leading to increased alcohol drinking behavior in the offspring. To our knowledge, this would be the first study to explore a role of the endocannabinoid system in the neurobiology of FASD. The proposed study will use a well-established alcohol binge model of FASD, in which the pregnant C57BL/6J mice will be given alcohol (2.9 g/kg twice daily, i.g.) on gestation days 7 and 8. The effect of alcohol exposure on the endocannabinoid system will be examined in the brain of offspring at adolescence and adult PD45 and PD90. This study will further evaluate whether prenatal alcohol exposure lead to an abnormal alcohol drinking behavior in offspring and if so, it is regulated by the endocannabinoid system. The proposed study is timely and findings may have a great potential in the development of therapeutic intervention in the treatment of behavioral deficits associated with prenatal alcohol exposure. PUBLIC HEALTH RELEVANCE: Abuse of alcohol during pregnancy has become a major health and social concern. The current proposal focuses on understanding a role of the endocannabinoid system in relation to neurochemical and behavioral changes resulting from prenatal alcohol exposure. The long-term goal of this study is to understand the cellular and molecular mechanism/s of FASD, especially alcohol-related behavior in offspring and to evaluate possible utility of the endocannabinoid system as a therapeutic target for the treatment of behavioral deficits associated with FASD.

描述（由申请人提供）：怀孕期间的滥用酒精（乙醇）与统称为胎儿酒精谱系（FASD）的广泛的与出生有关的缺陷有关，其特征是一系列发育缺陷包括颅面和心脏畸形。产前酒精暴露还会损害中枢神经系统（CNS）的发展，导致后代的几种异常行为，包括易受酒精滥用的脆弱性。这仍然是一个重大的临床挑战和一个重要的社会问题。尽管现在正在出现针对特定结果的干预措施，但目前尚无治疗全球胎儿酒精影响的临床疗法。尽管在描述有助于FASD的机制方面取得了一些进展，但我们知识的差距仍然很大程度上仍然存在。 最近发现的内源性大麻素系统已成为了解其在健康和疾病中的重要性方面的焦点。现在有积累的证据暗示内源性大麻素系统在包括酒精相关行为在内的几种神经精神疾病中的作用。我们的初步研究表明，在纹状体中内源性大麻素系统组成部分中的选择性异常，并且在子宫饮酒暴露的青春期后代小鼠中，饮酒行为较大。基于这些证据和我们的初步发现，我们假设妊娠期关键时期的酒精暴露会不利地影响内源性大麻素系统，这是一个其他靶标之一，导致后代的酒精饮酒行为增加。据我们所知，这将是第一个探索内源性大麻素系统在FASD神经生物学中的作用的研究。拟议的研究将使用良好的FASD酒精暴饮暴食模型，其中在妊娠第7和8天，怀孕的C57BL/6J小鼠每天两次给予酒精（每天两次）。酒精暴露对内ocannabinoid系统的影响将在适时和成人PD45和PD90和PD90和PD90和PD90的大脑中检查。这项研究将进一步评估产前酒精暴露是否导致后代的饮酒行为异常，如果是，则受内源性大麻素系统调节。拟议的研究是及时的，发现在治疗与产前酒精相关的行为缺陷方面可能具有巨大潜力。 公共卫生相关性：怀孕期间滥用酒精已成为主要的健康和社会关注。当前的提案着重于理解内源性大麻素系统在产前酒精暴露导致的神经化学和行为变化方面的作用。这项研究的长期目标是了解FASD的细胞和分子机制/s，尤其是后代中与酒精相关的行为，并评估内源性大麻素系统作为治疗与FASD相关的行为缺陷的治疗靶标。