@article{08803ce36fd7472986412a0de076f79b,
title = "Selected line difference in the effects of ethanol dependence and withdrawal on allopregnanolone levels and 5α-Reductase Enzyme Activity and Expression",
abstract = "Background: Allopregnanolone (ALLO) is a progesterone derivative that rapidly potentiates γ-aminobutyric acidA (GABAA) receptor-mediated inhibition and modulates symptoms of ethanol withdrawal. Because clinical and preclinical data indicate that ALLO levels are inversely related to symptoms of withdrawal, the present studies determined whether ethanol dependence and withdrawal differentially altered plasma and cortical ALLO levels in mice selectively bred for differences in ethanol withdrawal severity and determined whether the alterations in ALLO levels corresponded to a concomitant change in activity and expression of the biosynthetic enzyme 5α-reductase. Methods: Male Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mice were exposed to 72 hours ethanol vapor or air and euthanized at select times following removal from the inhalation chambers. Blood was collected for analysis of ALLO and corticosterone levels by radioimmunoassay. Dissected amygdala, hippocampus, midbrain, and cortex as well as adrenals were examined for 5α-reductase enzyme activity and expression levels. Results: Plasma ALLO was decreased significantly only in WSP mice, and this corresponded to a decrease in adrenal 5α-reductase expression. Cortical ALLO was decreased up to 54% in WSP mice and up to 46% in WSR mice, with a similar decrease in cortical 5α-reductase activity during withdrawal in the lines. While cortical gene expression was significantly decreased during withdrawal in WSP mice, there was a 4-fold increase in expression in the WSR line during withdrawal. Hippocampal 5α-reductase activity and gene expression was decreased only in dependent WSP mice. Conclusions: These results suggest that there are line and brain regional differences in the regulation of the neurosteroid biosynthetic enzyme 5α-reductase during ethanol dependence and withdrawal. In conjunction with the finding that WSP mice exhibit reduced sensitivity to ALLO during withdrawal, the present results are consistent with the hypothesis that genetic differences in ethanol withdrawal severity are due, in part, to modulatory effects of GABAergic neurosteroids such as ALLO.",
keywords = "Alcohol, GABA Receptors, Mouse, Neurosteroid, Radioimmunoassay",
author = "Tanchuck, {Michelle A.} and Long, {Season L.} and Ford, {Matthew M.} and Joel Hashimoto and Crabbe, {John C.} and Roselli, {Charles E.} and Wiren, {Kristine M.} and Finn, {Deborah A.}",
note = "Funding Information: GV Papatheodoridis : advisor/lecturer for Abbvie, Dicerna, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck Sharp & Dohme, Roche, Spring Bank; research grants Abbvie, Gilead. GN Dalekos : advisor/lecturer for Abbvie, Bayer, Bristol-Myers Squibb, Gilead, Janssen, Novartis, Roche; grant support from Bristol-Myers Squibb, Gilead, Roche. R Idilman : Nothing to declare. V Sypsa : advisor/lecturer for Abbvie, Gilead, Janssen; research grants from Abbvie, Gilead. F van Boemmel: advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme, Novartis, Roche; research grants from Bristol- Myers Squibb, Gilead, Janssen, Roche, Siemens; consultant for Abbvie, Gilead, Roche. M Buti : advisor/lecturer for Abbvie, Arbutus, Bristol-Myers Squibb, Gilead, Glaxo Smith-Kleine, Merck, Roche, Spring Bank. JL Calleja : advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck. J Goulis : advisor/lecturer for Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Roche; research grant from Bristol-Myers Squibb. S Manolakopoulos : advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche; grants from Bristol-Myers Squibb, Gilead. A Loglio: lecturer for Gilead, MYR Pharmaceuticals. M Papatheodoridi : Nothing to declare. N Gatselis : advisor for Gilead. R Veelken : Nothing to declare. M Lopez-Gomez : Nothing to declare. BE Hansen : Nothing to declare. S Savvidou : Nothing to declare. A Kourikou : Nothing to declare. I Vlachogiannakos : advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Merck Sharp & Dohme, Novartis, Roche. K Galanis : Nothing to declare. C Yurdaydin : speaker's bureau and/or advisor for AbbVie, Bristol-Myers Squibb, Gilead, Merck, Roche; research grant from Bristol-Myers Squibb. R Esteban : advisor/lecturer for Abbvie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis. HLA Janssen : consultant for and grants from AbbVie, Arbutus, Bristol-Myers Squibb, Enyo, Gilead Sciences, Janssen, Medimmune, Merck, Roche, Vir Biotechnology Inc., Viroclinics. T Berg : advisor/consultant/lecturer for Abbvie, Alexion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck Sharp & Dohme/Merck, Novartis, Roche, and Vertex; Research support from Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme/Merck, Novartis and Roche. P Lampertico : speaking bureau/advisor for Abbvie, Eiger, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck/Merck Sharp & Dohme, MYR Pharma, Roche. ",
year = "2009",
month = dec,
doi = "10.1111/j.1530-0277.2009.01047.x",
language = "English (US)",
volume = "33",
pages = "2077--2087",
journal = "Alcoholism: Clinical and Experimental Research",
issn = "0145-6008",
publisher = "Wiley-Blackwell",
number = "12",
}