FAS children exhibit behavioral deficits that are indicative of impaired development of neurotransmitter systems. In rodents, ethanol exposure produces a remarkable (45-65 percent) decrease of serotonin content in the raphe neurons of the fetal brainstem. This reduction is important because 5-HT is an essential trophic factor for serotonergic neurons; reductions in 5-HT impair the development of raphe neurons and the density of their projects. Maternal administration of buspirone, a 5- HT1A agonist, prevents many of the 5-HT deficits that arise from in utero ethanol exposure. This proposal will test the hypothesis that buspirone prevents the damaging effects of ethanol on developing 5-HT neurons through its stimulation of astroglial 5-TH1A receptors and subsequent release of astroglial trophic factors, notably the glial growth factor S-100beta. S-100beta plays an essential role in the development of the serotonergic system. In vivo studies have shown that disruption of S-100beta production impairs the development of the 5-HT system. The three aims of this proposal will: (1) determine whether astroglial production of S-100beta in the Midline Raphe Glial Structure is impaired by in utero ethanol exposure, and whether buspirone prevents this effect of ethanol, (2) determine whether ethanol inhibits the paracrine effects of astroglia factors that normally result in increased production of S-100beta, and whether buspirone prevents these effects of ethanol, and (3) determine whether buspirone treatment of astrocytes prevents the reduced production/secretion of astrocytic neurotrophic factors. Results from these studies will contribute to our understanding of the mechanism by which ethanol exerts its damaging effects on the 5-HT system.
