Role of the Endocannabinoid Signaling in Fetal Alcohol Spectrum Disorders

描述（由申请人提供）：妊娠期间滥用酒精（乙醇）与广泛的出生相关缺陷有关，统称为胎儿酒精谱系障碍（FASD），其特征是一系列发育缺陷，包括颅面和心脏畸形。产前酒精暴露也会损害中枢神经系统（CNS）的发育，导致后代出现几种异常行为，包括易受酒精滥用的影响。它仍然是一个重大的临床挑战和重要的社会问题。虽然针对特定结局的干预措施正在出现，但目前还没有治疗全球胎儿酒精影响的临床疗法。尽管在界定导致FASD的机制方面取得了一些进展，但我们的知识差距仍然很大。 最近发现的内源性大麻素系统已成为深入研究的焦点，以了解其在健康和疾病中的重要性。现在有越来越多的证据表明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起作用。我们的初步研究表明，选择性异常成分的内源性大麻素系统在纹状体和更大的饮酒行为在子宫内酒精暴露的青春期后代小鼠。基于这些证据和我们的初步研究结果，我们假设在妊娠的关键时期，酒精暴露对内源性大麻素系统产生不利影响，这是许多其他目标之一，导致后代饮酒行为增加。据我们所知，这将是第一项探索内源性大麻素系统在FASD神经生物学中作用的研究。所提出的研究将使用FASD的良好建立的酒精狂欢模型，其中妊娠C57 BL/6 J小鼠将被给予酒精（2.9g/kg，每日两次，i.g.）在妊娠第7天和第8天。酒精暴露对内源性大麻素系统的影响将在青春期和成年PD 45和PD 90的后代大脑中进行检查。本研究将进一步评估产前酒精暴露是否会导致后代的异常饮酒行为，如果是这样，它是由内源性大麻素系统调节的。拟议的研究是及时的，研究结果可能有很大的潜力，在治疗与产前酒精暴露相关的行为缺陷的治疗干预的发展。 与公共卫生的相关性：怀孕期间酗酒已成为一个主要的健康和社会问题。目前的建议侧重于了解内源性大麻素系统在产前酒精暴露引起的神经化学和行为变化中的作用。本研究的长期目标是了解FASD的细胞和分子机制，特别是后代的酒精相关行为，并评估内源性大麻素系统作为治疗FASD相关行为缺陷的治疗靶点的可能效用。

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.