PRENATAL ETHANOL EXPOSURE ALTERS THE MODULATION OF THE GAMMA-AMINOBUTYRIC ACID(A) RECEPTOR-GATED CHLORIDE-ION CHANNEL IN ADULT-RAT OFFSPRING

We examined the effect of prenatal ethanol exposure on gamma-aminobuty ric acid (GABA)-stimulated Cl-36(-) flux. Sprague-Dawley rat dams were fed either a liquid diet containing 5% ethanol, pair-fed an isocalori cally equivalent 0% ethanol diet or rat chow ad libitum throughout ges tation. Membrane vesicles were prepared from medial frontal cortex, ce rebellum and hippocampal formation of adult offspring in each diet gro up, GABA-stimulated Cl-36(-) flux was not significantly affected by pr enatal ethanol exposure in any of the three brain regions examined, Po sitive allosteric modulation of GABA-stimulated Cl-36(-) flux by fluni trazepam or alphaxalone, as well as negative modulation by FG-7142 or pregnenolone, were all diminished in medial frontal cortex of 5% ethan ol diet offspring compared with both ad libitum and pair-fed control g roups. in cerebellum, prenatal ethanol exposure attenuated the modulat ory effects of both benzodiazepines, but did not affect neurosteroid m odulation. In hippocampus, prenatal ethanol exposure enhanced the effe cts of flunitrazepam and alphaxalone, whereas negative modulatory effe cts were either decreased (FG-7142) or unchanged (pregnenolone). These results indicate that moderate ethanol consumption during gestation c an produce long-lasting alterations in neuromodulatory influences on G ABA, receptor-mediated inhibitory neurotransmission in adult offspring , In hippocampal formation, the heightened sensitivity to positive mod ulatory influences may contribute to synaptic plasticity deficits in f etal ethanol-exposed rat offspring, We speculate that these prenatal e thanol-induced changes may be either a consequence of differential GAB A, receptor subunit expression or receptor uncoupling in different bra in regions. Furthermore, offspring exposed to ethanol in utero may dis play differential sensitivities to benzodiazepines and possibly other centrally active therapeutic agents.