In utero ethanol exposure adversely affects the development of several CNS neurotransmitter systems, including those that use serotonin (5-HT) and dopamine (DA). For ethanol to impair the development of many neurotransmitter systems, it likely acts via multiple mechanisms or by altering the level of a hormone or factor which is essential to the development of several neuronal types. This grant will examine the hypothesis that in utero ethanol exposure adversely affects the development of the serotonergic, dopaminergic, and other neurotransmitter systems by altering the content of one or more essential neurotrophic factors (NTF). The proposed research is a logical extension of our previous studies, which demonstrated that in utero ethanol exposure decreases the level of fetal 5-HT. Fetal 5-HT functions as a trophic factor, which is essential for the normal development of serotonergic neurons, their targets and nonserotonergic neurons. The proposed research is also based on evidence from this and other laboratories that ethanol decreases astroglial protein synthesis, and the knowledge that several astroglial-produced neurotrophic factors are essential to the survival of serotonergic and dopaminergic neurons, as well as other CNS neurons. To test the hypothesis, we propose to comprehensively assess the development of the serotonergic system in the offspring of control and ethanol-fed rats, that were treated with a 5-HT1A agonist during pregnancy. This research will include HPLC analyses of neurotransmitter content, and quantitative autoradiographic analyses of 5-HT uptake sites and the 5-HT1A and 5-HT2 receptors. This grant will also include a limited study of the effects of in utero 5-HT1A agonist treatment on the dopaminergic and noradrenergic systems, to determine whether 5-HT1A agonist treatment can prevent some of the observed abnormalities in these systems. In addition, we will determine whether altered astroglial production of essential NTFs contributes to the ethanol-associated abnormal development of rhombencephalic (5-HT) neurons and mesencephalic (DA) neurons, as well as other neurons in the same brain areas. This will be investigated by assessing the effects of serum-free conditioned media (CM), obtained from control and ethanol-exposed cultured astroglia, on neuron survival and neurite outgrowth as well as on neurotransmitter (5-HT, DA) content and reuptake, and 5-HT- and tyrosine hydroxylase-immunopositive neurons.
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