Role of the Endocannabinoid Signaling in Fetal Alcohol Spectrum Disorders

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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.