Selected line difference in the effects of ethanol dependence and withdrawal on allopregnanolone levels and 5α-Reductase Enzyme Activity and Expression

Michelle A. Tanchuck, Season L. Long, Matthew Ford, Joel Hashimoto, John Jr Crabbe, Charles Roselli, Kristine Wiren, Deborah (Deb) Finn

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2077-2087
Number of pages11
JournalAlcoholism: Clinical and Experimental Research
Volume33
Issue number12
DOIs
StatePublished - Dec 2009

Fingerprint

Pregnanolone
Enzyme activity
Oxidoreductases
Ethanol
Seizures
Enzymes
Substance Withdrawal Syndrome
Gene expression
Neurotransmitter Agents
Plasmas
Gene Expression
GABA-A Receptors
Corticosterone
Mesencephalon
Amygdala
Inhalation
Radioimmunoassay
Progesterone
Hippocampus
Brain

Keywords

  • Alcohol
  • GABA Receptors
  • Mouse
  • Neurosteroid
  • Radioimmunoassay

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

@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 Matthew Ford and Joel Hashimoto and Crabbe, {John Jr} and Charles Roselli and Kristine Wiren and Finn, {Deborah (Deb)}",
year = "2009",
month = "12",
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",

}

TY - JOUR

T1 - Selected line difference in the effects of ethanol dependence and withdrawal on allopregnanolone levels and 5α-Reductase Enzyme Activity and Expression

AU - Tanchuck, Michelle A.

AU - Long, Season L.

AU - Ford, Matthew

AU - Hashimoto, Joel

AU - Crabbe, John Jr

AU - Roselli, Charles

AU - Wiren, Kristine

AU - Finn, Deborah (Deb)

PY - 2009/12

Y1 - 2009/12

N2 - 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.

AB - 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.

KW - Alcohol

KW - GABA Receptors

KW - Mouse

KW - Neurosteroid

KW - Radioimmunoassay

UR - http://www.scopus.com/inward/record.url?scp=70450196493&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70450196493&partnerID=8YFLogxK

U2 - 10.1111/j.1530-0277.2009.01047.x

DO - 10.1111/j.1530-0277.2009.01047.x

M3 - Article

VL - 33

SP - 2077

EP - 2087

JO - Alcoholism: Clinical and Experimental Research

JF - Alcoholism: Clinical and Experimental Research

SN - 0145-6008

IS - 12

ER -