Cognitive impairment and increased brain neurosteroids in adult rats perinatally exposed to low millimolar blood alcohol concentrations

Epidemiological evidence suggests that adolescents and adults perinatally exposed to alcohol., even at low doses, show high prevalence of cognitive impairment and social behavior deficits, which may be in part related to alcohol.-induced changes of the 7-aminobutyric acid (GABA)ergic neurotransmission. The endogenous neurosteroid 3 alpha-hydroxy,5 alpha-pregnan-20-one (3 alpha,5 alpha-tetrahydroprogesterone/3 alpha,5 alpha-THP), a potent positive allosteric modulator of GABA(A) receptor function, is implicated in the physiological tuning of GABA-mediated fast inhibition and in various alcohol's actions in the brain. This study was undertaken to determine whether perinatal exposure to low millimolar blood alcohol concentrations alters cognitive skills (social, discrimination and inhibitory avoidance tests), emotional. reactivity (elevated plus maze test), and neurosteroid content in brain cortex and hippocampus of adult mate offspring. Dams had access to a 3% alcohol solution or to an equicaloric sucrose solution from gestational day 15 to postnatal day 9. Eighty-day old alcohol-exposed mate offspring exhibited impaired social recognition memory, but unchanged inhibitory avoidance performance and normal behavior on the elevated-plus maze. The concentrations of 3 alpha,5 alpha-THP and its precursor progesterone were more than doubted in brain cortex and hippocampus of atcohol-exposed rats, whereas in plasma only progesterone was increased. Thus, exposure to tow millimolar blood alcohol concentrations has a tong-tasting impact on the developing brain as it causes an impairment of social recognition as well as an increase of brain neurosteroid content in mature animals. The tatter may be consequent to altered expression /activity of brain steroidogenic enzymes, as reflected by the enduring increase of the GABAA receptor-active neurosteroid 3 alpha,5 alpha-THP in brain cortex and hippocampus, but not in plasma. It is speculated that, by inducing a greater amplification of GABA(A) receptor function, the elevation of 3 alpha,5 alpha-THP brain content contributes to the cognitive impairment exhibited by adult alcohol-exposed offspring. (C) 2007 Elsevier Ltd. All rights reserved.