Exposure to alcohol during gestation can result in a variety of structural and functional changes. The most well known are those associated with the fetal alcohol syndrome (FAS), which include growth retardation, CMS dysfunction, and a distinct facial appearance. Undoubtedly, the most devastating consequences are those involving the central nervous system (CMS). Both human studies and those employing animal model systems demonstrate a number of alterations in brain and behavioral outcomes. Despite a large number of studies describing the changes seen following prenatal alcohol exposure, few studies have investigated possible treatments for these alcohol- induced changes. We plan on continuing our work examining the hypothesis that withdrawal from alcohol may play a role in these effects. We have demonstrated that blockade of the NMDA receptor with the noncompetitive antagonist MK-801 during ethanol withdrawal prevents some of the behavioral and neuropathological effects resulting from perinatal alcohol exposure, but that these effects are dose and time dependent. Mitigating effects are only seen with lower doses and administration when the blood alcohol levels are nearing 0 mg/dl. Higher doses and administration at the same time as ethanol can be toxic or even lethal. We now plan on examining, memantine, a novel NMDA antagonist that seems to have few of the side effects of other NMDA antagonists, thus it may be useful clinically. A series of studies are proposed in which a variety of behavioral and neuroanatomical measures are assessed. The first study examines the dose-response properties of memantine, the next study examines the time course of action of memantine, and the third involves chronic vs. acute exposure. A parallel line of study will examine the neuropathological changes in relevant brain regions following these treatments. All studies utilize an animal model system of third trimester exposure. These studies, if successful, will provide additional support for withdrawal as one mechanism of ethanol's teratogenicity and provide data regarding a possible treatment to mitigate some of the teratogenic effects of alcohol. ? ?
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