title: Corticosterone increases damage and cytosolic calcium accumulation associated with ethanol withdrawal in rat hippocampal slice cultures.
abstract: BACKGROUND
  Evidence suggests that stress hormones (i.e., glucocorticoids) may be increased during acute or chronic consumption of ethanol and during withdrawal from ethanol consumption, effects that may contribute to the development of cognitive impairment. The goal of the current studies was to examine the hypothesis that increased glucocorticoid levels in conjunction with ethanol exposure and withdrawal may cause hippocampal damage.
  
  
  METHODS
  Organotypic hippocampal slice cultures were exposed to 50 mM ethanol for 10 days and withdrawn for 1 day. After withdrawal, cytotoxicity and cytosolic Ca2+ accumulation were measured using the nucleic acid stain propidium iodide and Calcium Orange, AM, respectively. Cultures were also treated with nontoxic concentrations of corticosterone (0.001-1 microM) during ethanol exposure and withdrawal or only during withdrawal. Additional cultures were coexposed to corticosterone and RU486 (0.1-10.0 microM), spironolactone (0.1-10.0 microM), or MK-801 (20 microM) during ethanol exposure and/or withdrawal.
  
  
  RESULTS
  Ethanol withdrawal did not increase propidium iodide fluorescence and cytosolic Ca2+ levels. However, significant increases in propidium iodide fluorescence and in cytosolic Ca2+ accumulation were observed in cultures when corticosterone (> or = 100 nM) was exposed during ethanol treatment and/or withdrawal. These effects of corticosterone on ethanol withdrawal were attenuated by RU486 and MK-801 but not by spironolactone coexposure.
  
  
  CONCLUSIONS
  This report demonstrated that corticosterone exposure during ethanol treatment and/or withdrawal resulted in significant hippocampal damage, possibly via activation of glucocorticoid receptors and enhancement of the glutamatergic cascade. The findings from these studies suggest that glucocorticoids contribute to the neuropathological consequences of alcohol dependence in humans.
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, Kentucky 40506-0044, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Mulholland
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Self
authors.forename: Barton R
authors.initials: BR
authors.lastname: Harris
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Little
authors.forename: John M
authors.initials: JM
authors.lastname: Littleton
authors.forename: Mark A
authors.initials: MA
authors.lastname: Prendergast
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D005456:Fluorescent Dyes; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009924:Organ Culture Techniques; D009930:Organic Chemicals; D011419:Propidium; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000473:pathology*
chemical_list: D002492:Central Nervous System Depressants; D005456:Fluorescent Dyes; D006727:Hormone Antagonists; D000451:Mineralocorticoid Receptor Antagonists; D009930:Organic Chemicals; D011965:Receptors, Glucocorticoid; D016194:Receptors, N-Methyl-D-Aspartate; C071335:calcium orange; D013148:Spironolactone; D015735:Mifepristone; D011419:Propidium; D000431:Ethanol; D002118:Calcium; D003345:Corticosterone