Many studies of fetal alcohol syndrome (FAS) emphasize the relationship between the severity of abnormalities and the timing of ethanol administration relative to vulnerable periods in brain development. Chronic in utero ethanol exposure markedly impairs the early development of the serotonin (5-HT) system by encompassing a critical vulnerable period. During this period, 5-HT neurons are generated, differentiate, and extend projections to target areas; also during this period 5-HT normally exerts neurotrophic effects by stimulating astrocyte 5HT/1A receptors to increase production of S100beta, a neurotrophic factor (NTF) that is essential for the normal development of 5-HT neurons. Despite the frequency of FAS and the tremendous public health costs associated with FAS, there is no therapeutic treatment that prevents the CNS damage. This grant will investigate a mechanism by which ethanol may impair the development of the 5-HT system and a therapeutic intervention that may prevent this damage. A potential mechanism underlying the aberrant development of the 5-HT system is an ethanol-induced reduction of S100beta. This grant will investigate the use of a 5-HT/1A agonist because research suggests that this agonist prevents ethanol-associated damage to the developing 5-HT system in rats, and because this agonist increases production of S100beta. This grant proposal will investigate the following questions: Does ethanol impair the astrocyte-mediated neurotrophic stimulation of the development of serotonergic neurons? Can the damaging effects of ethanol be prevented by stimulation with a 5-HT/1A agonist? These questions will be examined using both an in vivo and in vitro experiments. In vivo experiments use a rat model to assess the effects of in utero ethanol exposure on the development of 5-HT neurons and astrocyte production of S100beta; Separate in vitro studies will use astrocytes, neurons, and astrocyte-neuron co-cultures to identify the cellular level at which these effects are mediated. Analyses will include in situ hybridization, northern and western blots, immunohistochemistry, [3H]5-HT reuptake, HPLC, and cell culture.
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