To elucidate the neurochemical cause(s) of the CNS abnormalities associated with the fetal alcohol syndrome (FAS), this laboratory has studied the serotonergic (5-HT) system the developing offspring of rats that consumed an ethanol-containing liquid diet on a chronic basis prior to parturition. These studies have shown that the 19- and 35-day-old ethanol-exposed rats have a cortical deficiency of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA). 5-HT uptake sites, and 5-HTl binding sites, but a normal number of 5- HT2 binding sites. These results suggest that in utero ethanol exposure decreases serotonergic projections to the cortex and hence results in a decrease in 5-HT containing terminals. Since 5-HT is an important embryonic factor which promotes neuronal maturation as well as collateral formation between neighboring 5- HT neurons, the observed postnatal serotonergic abnormalities may be due to lack of the embryonic 5-HT signal, or to lack of a receptor response to the 5-HT signal. Thus, the proposed studies will determine how in utero ethanol exposure affects the embryonic development of 5-HT, 5-HTl binding sites, and 5-HT autoreceptor function. (5-HT will be assessed using HPLC. Binding sites will be studied using radioligand techniques. Studies of autoreceptor function will assess K+- stimulated release of (3H)-5-HT.) Additional studies will determine whether prenatal administration of one of three 5-HT agonist (quipazine, 8-OH-DPAT or TFMPP) can overcome or prevent the effects of in utero ethanol exposure. These experiments are important because they will assess potential cause(s) of CNS abnormalities associated with in utero ethanol exposure and possible therapeutic treatments. Additional studies are directed towards elucidating the nature of the postnatal cellular/functional damage caused by in utero ethanol exposure. These studies will determine which of the cortical 5- HT1 receptor subtypes is decreased by in utero ethanol exposure, whether the 5-HT1 receptor deficiency is reflected in altered autoreceptor function, and whether 5-HT stimulation of 2nd messenger (IP3) formation and protein phosphorylation are also affected by in utero ethanol exposure. Finally, presynaptic 5-HT terminals will be selectively destroyed, using chemical denervation, in order to determine whether the 5-HT1 receptor deficiency corresponds to a pre- and/or postsynaptic localization.
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