Mental retardation and abnormal CNS development are consistent features of the fetal alcohol syndrome (FAS). The rat hippocampus will be used as a model system to investigate the central nervous system abnormalities induced by ethanol exposure in the fetal alcohol syndrome. 6 gm/kg ethanol was administered daily to pregnant rats from days 1 to 15 of pregnancy. Progeny were raised to 25 days of postnatal age and their hippocampi isolated and pre-incubated for 30 min at 37 C in Eagle's Medium containing 5 mM theophylline and 2.2 mM CaCl2. They were then incubated in the same solution plus 500 MuM bethanechol for 2.5 min and analyzed for cyclic GMP by radioimmunoassay. These conditions produce a maximal cyclic GMP response. Controls were rat pups whose mothers had received isocaloric sucrose instead of ethanol during pregnancy. Exposure to ethanol in utero from days 1 to 15 resulted in a significant decrease in the cyclic GMP response. An 18% decrease in the number of pyramidal cells in the hippocampus has been reported under similar ethanol exposure. Since the pyramidal cells synthesize cyclic GMP, these results show that intrauterine ethanol exposure leads to persistent alteration in the development of hippocampal neurons and their cyclic GMP responsiveness. This research will help answer the following questions: (1) What is the effect of administration of 6 gm/kg/day ethanol to pregnant rats by intragastric intubation on the maximal cyclic GMP response of their progeny on different days of postnatal age? (2) What are the effects of administration of ethanol to pregnant rats as 40% of the calories consumed in a liquid diet during days 1-12 of pregnancy on the cyclic GMP response of hippocampal neurons of their progeny? Days 13 to 21? (3) What are the critical developmental periods when the fetal hippocampus is most vulnerable to ethanol? (4) What is the minimum maternal dose (threshold) of ethanol for derangement of the maximal cyclic GMP response (""""""""safe"""""""" levels of maternal ethanol consumption)? Since the maximal cyclic GMP response depends on the levels of muscatinic cholinergic receptors present, these will be determined using the quinuclidinyl benzilate technique for all time and dosage points of interest. Blood ethanol determinations will be performed as well, using a second group of rats to avoid additional stress on the experimental animals.
