In vitro and In vivo models for ethanol withdrawal and antepartum hypoxia

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorder describes a wide range of behaviors and deficits that can occur as a consequence of prenatal alcohol exposure. These effects can range from relatively subtle learning deficits to significant mental retardation. Various explanations for differences in sensitivity to alcohol's effects have been proposed. One theory suggests that "provocative factors" can play a role in increasing the severity and/or providing a context in which the damaging effects of ethanol are increased. We propose that prenatal alcohol exposure may increase the adverse consequences of brief periods of hypoxia during the antepartum period when brief periods of hypoxia routinely occur. Normally, the fetus/newborn is fairly resilient against mild hypoxia during labor and delivery, however, additional challenges (such as a history of in utero alcohol exposure or alcohol withdrawal) may put these infants at increased risk for adverse outcome. In this application, we propose to develop two models. The first is an in vitro organotypic hippocampal slice culture model taken from 1-day-old rats. These cultures will be exposed to chronic alcohol, followed by withdrawal and challenged with oxygen glucose deprivation (as a model of hypoxia). The hypothesis is that alcohol and hypoxia will produce greater damage than exposure to either challenge alone. Sub-threshold doses will also be included in this Specific Aim to assess the sensitivity of the hippocampus to these challenges. The 2nd model we will develop involves three trimester in vivo administration of alcohol first to pregnant dams and then to Sprague Dawley rat pups on postnatal day 1-7. Following alcohol withdrawal, the pups will also be exposed to a mild hypoxic challenge and subsequently tested for a variety of behavioral endpoints including activity and measures of learning and memory. Our working hypothesis is that alcohol exposure and/or withdrawal and hypoxic challenges share similar mechanisms (including overactivity of NMDAR, increased GLU activity and polyamine release) that could result in increased excitotoxic damage. The studies proposed will allow us to determine the potential validity of these models. In addition, once we have established these models, we can begin to study the underlying mechanisms and potential pharmacotherapeutic interventions to try and reduce the damage/deficits associated with alcohol withdrawal and hypoxia. These data could have significant clinical potential since our premise (and model) focuses on a relatively narrow developmental window which conceptually overlaps a time when women would typically be seeking medical assistance (i.e. labor and delivery) and intervention would be more likely. PUBLIC HEALTH RELEVANCE: Mild bouts of hypoxia (or reduced oxygen availability) commonly occur during normal labor and delivery and the newborn is usually not affected by these if the bouts are not severe. We propose that one of the effects of prenatal alcohol exposure is to increase the risk of these minor bouts resulting in behavioral and CNS damage. The studies in this application will develop cell culture and rodent models to begin to address this clinically-relevant question.