Prenatal Ethanol Exposure Alters the Modulation of the g- Aminobutyric AcidA Receptor-Gated Chloride Ion Channel in Adult Rat Offspring

We examined the effect of prenatal ethanol exposure on g-aminobutyric acid (GABA)-stimulated Cl flux. Sprague-Dawley rat dams were fed either a liquid diet containing 5% ethanol, pair-fed an isocalorically equivalent 0% ethanol diet or rat chow ad libitum throughout gestation. Membrane vesicles were prepared from medial frontal cortex, cerebellum and hippocampal formation of adult offspring in each diet group. GABA-stimulated Cl flux was not significantly affected by prenatal ethanol exposure in any of the three brain regions examined. Positive allosteric modulation of GABA-stimulated Cl flux by flunitrazepam or alphaxalone, as well as negative modulation by FG-7142 or pregnenolone, were all diminished in medial frontal cortex of 5% ethanol diet offspring compared with both ad libitum and pair-fed control groups. In cerebellum, prenatal ethanol exposure attenuated the modulatory effects of both benzodiazepines, but did not affect neurosteroid modulation. In hippocampus, prenatal ethanol exposure enhanced the effects of flunitrazepam and alphaxalone, whereas negative modulatory effects were either decreased (FG-7142) or unchanged (pregnenolone). These results indicate that moderate ethanol consumption during gestation can produce long-lasting alterations in neuromodulatory influences on GABAA receptor-mediated inhibitory neurotransmission in adult offspring. In hippocampal formation, the heightened sensitivity to positive modulatory influences may contribute to synaptic plasticity deficits in fetal ethanol-exposed rat offspring. We speculate that these prenatal ethanol-induced changes may be either a consequence of differential GABAA receptor subunit expression or receptor uncoupling in different brain regions. Furthermore, offspring exposed to ethanol in utero may display differential sensitivities to benzodiazepines and possibly other centrally active therapeutic agents. The developing brain is extremely sensitive to the effects of ethanol (Abel, 1984; West and Pierce, 1986). Heavy consumption of ethanol during pregnancy can result in a set of profound morphological and neurological aberrations called fetal alcohol syndrome (Lemoine et al., 1968; Jones and Smith, 1973; Jones et al., 1973; Clarren and Smith, 1978). Further, there is a growing appreciation for the concern that moderate ethanol consumption may cause subtle, long-term impairments in the absence of the gross morphological or neurological defects associated with FAS (Shaywitz et al., 1980; Abel, 1984). For example, moderate ethanol exposure in utero causes cognitive deficits in children which may not become apparent until the child is challenged during the educational years (Streissguth et al., 1990; Conry, 1990) and may increase in severity as the child matures (Streissguth et al., 1991, 1994). Recognition of this problem led to the recommendation that the diagnostic classification of fetal alcoholrelated defects be expanded to include a new category called alcohol-related neurodevelopmental disorders (ARND; Strat-