title: Chronic prenatal ethanol exposure increases glucocorticoid-induced glutamate release in the hippocampus of the near-term foetal guinea pig.
abstract: Exposure to high cortisol concentration can injure the developing brain, possibly via an excitotoxic mechanism involving glutamate (Glu). The present study tested the hypothesis that chronic prenatal ethanol exposure (CPEE) activates the foetal hypothalamic-pituitary-adrenal axis to produce high cortisol exposure in the foetal compartment and alters sensitivity to glucocorticoid-induced Glu release in the foetal hippocampus. Pregnant guinea pigs received daily oral administration of ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding from gestational day (GD) 2 until GD 63 (term, approximately GD 68) at which time they were euthanised, 1 h after their final treatment. Adrenocorticotrophic hormone (ACTH) and cortisol concentrations were determined in foetal plasma. Basal and electrically stimulated Glu and gamma-aminobutyric acid (GABA) efflux in the presence or absence of dexamethasone (DEX), a selective glucocorticoid-receptor agonist, were determined ex vivo in foetal hippocampal slices. Glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and N-methyl-D-aspartate (NMDA) receptor NR1 subunit mRNA expression were determined in situ in the hippocampus and dentate gyrus. In the near-term foetus, CPEE increased foetal plasma ACTH and cortisol concentrations. Electrically stimulated glutamate, but not GABA, release was increased in CPEE foetal hippocampal slices. Low DEX concentration (0.3 microM) decreased stimulated glutamate, but not GABA, release in both CPEE and control foetal hippocampal slices. High DEX concentration (3.0 microM) increased basal release of Glu, but not GABA, in CPEE foetal hippocampal slices. GR, but not MR, mRNA expression was elevated in the hippocampus and dentate gyrus, whereas NR1 mRNA expression was increased in the CA1 and CA3 fields of the foetal hippocampus. These data demonstrate that CPEE increases high glucocorticoid concentration-induced Glu release in the foetal hippocampus, presumably as a consequence of increased GR expression. These effects of CPEE, coupled with increased glutamate release and increased NMDA receptor expression, may predispose the near-term foetal hippocampus to GR and Glu-NMDA receptor-mediated neurodevelopmental toxicity.
authors.affiliation: Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors.forename: U
authors.initials: U
authors.lastname: Iqbal
authors.forename: J F
authors.initials: JF
authors.lastname: Brien
authors.forename: A
authors.initials: A
authors.lastname: Kapoor
authors.forename: S G
authors.initials: SG
authors.lastname: Matthews
authors.forename: J N
authors.initials: JN
authors.lastname: Reynolds
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D002492:Central Nervous System Depressants / Q000633:toxicity; D004558:Electric Stimulation; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D018698:Glutamic Acid / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D009498:Neurotoxins / Q000633:toxicity*; D009924:Organ Culture Techniques; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D018709:Statistics, Nonparametric; D036401:Toxicity Tests, Chronic
chemical_list: D002492:Central Nervous System Depressants; D005938:Glucocorticoids; D009498:Neurotoxins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D018698:Glutamic Acid; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone