title: Binge-like ethanol consumption increases corticosterone levels and neurodegneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective.
abstract: Excessive ethanol (EtOH) use leads to impaired memory and cognition. Using a rat model of binge-like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing Cort in order to achieve basal, medium, or high blood concentrations of Cort. Intragastric EtOH or an isocaloric control solution was given three times daily for 4 days to achieve blood alcohol levels ranging between 200 and 350 mg/dl. Mean 24-hour plasma levels of Cort were ∼110 and ∼40 ng/ml in intact EtOH-treated and intact control animals, respectively. Basal Cort replacement concentrations in EtOH-treated Adx animals did not exacerbate alcohol-induced neurodegeneration in the hippocampal dentate gyrus (DG) or the entorhinal cortex (EC) as observed by amino-cupric silver staining. In contrast, Cort replacement pellets resulting in plasma Cort levels twofold higher (medium) than normal, or greater than twofold higher (high) in Adx-Cort-EtOH animals increased neurodegeneration. In separate experiments, pharmacological blockade of the Type II glucocorticoid (GC) receptor was initiated with mifepristone (RU38486; 0, 5, 15 mg/kg/day, i.p.). At the higher dose, mifepristone decreased the number of degenerating hippocampal DG cells in binge-EtOH-treated intact animals, whereas, only a trend for reduction was observed in 15 mg/kg/day mifepristone-treated animals in the EC, as determined by fluoro-jade B staining. These results suggest that elevated circulating Cort in part mediates EtOH-induced neurotoxicity in the brain through activation of Type II GC receptors.
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cippitelli
authors.forename: Ruslan
authors.initials: R
authors.lastname: Damadzic
authors.forename: Carol
authors.initials: C
authors.lastname: Hamelink
authors.forename: Michael
authors.initials: M
authors.lastname: Brunnquell
authors.forename: Annika
authors.initials: A
authors.lastname: Thorsell
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.forename: Robert L
authors.initials: RL
authors.lastname: Eskay
mesh_terms: D000315:Adrenalectomy; D020268:Alcohol-Induced Disorders, Nervous System / Q000209:etiology; D000435:Alcoholic Intoxication / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D063425:Binge Drinking / Q000150:complications; D002784:Cholesterol / Q000008:administration & dosage; D003345:Corticosterone / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants / Q000008:administration & dosage; D018728:Entorhinal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D005452:Fluoresceins; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology*; D018696:Neuroprotective Agents; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D016622:Silver Staining; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology
chemical_list: D004343:Drug Implants; D005452:Fluoresceins; D006727:Hormone Antagonists; D018696:Neuroprotective Agents; D011965:Receptors, Glucocorticoid; C435731:fluoro jade; D015735:Mifepristone; D000431:Ethanol; D002784:Cholesterol; D003345:Corticosterone