Withdrawal severity after chronic intermittent ethanol in inbred mouse strains

Pamela Metten, Michelle L. Sorensen, Andy J. Cameron, Chia Hua Yu, John Jr Crabbe

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background: To study withdrawal, ethanol is usually administered chronically without interruption. However, interest has recurred in models of episodic exposure. Increasing evidence suggests that chronic intermittent exposure to ethanol leads to a sensitization effect in both withdrawal severity and ethanol consumption. The goal of the present study was to examine mouse inbred strain differences in withdrawal severity following chronic intermittent exposure using the handling-induced convulsion as the behavioral endpoint. We also sought to compare the withdrawal responses of inbred strains across acute, chronic continuous, and chronic intermittent exposure regimens. Methods: Male mice from 15 standard inbred strains were exposed to ethanol vapor for 16 hours each day for 3 days and removed to an air chamber during the intervening 8 hours. Mice in the control groups were handled the same, except that they were exposed only to air. Daily blood ethanol concentrations were averaged for each mouse to estimate total dose of ethanol experienced. Results: Across strains, mice had an average daily blood ethanol concentration (BEC) of 1.45 ± 0.02 mg/ml and we restricted the range of this value to 1.00-2.00 mg/ml. To evaluate strain differences, we divided data into two dose groups based on BEC, low dose (1.29 ± 0.1 mg/ml) and high dose (1.71 ± 0.02 mg/ml). After the third inhalation exposure, ethanol-exposed and air-exposed groups were tested hourly for handling-induced convulsions for 10 hour and at hour 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of air control values) in both dose groups. Conclusion: The chronic intermittent exposure paradigm is sufficient to elicit differential withdrawal responses across nearly all strains. Data from the high-dose groups correlated well with withdrawal data derived from prior acute (single high dose) and chronic continuous (for 72 hours) ethanol withdrawal studies, supporting the influence of common genes on all three responses.

Original languageEnglish (US)
Pages (from-to)1552-1564
Number of pages13
JournalAlcoholism: Clinical and Experimental Research
Volume34
Issue number9
DOIs
StatePublished - Sep 2010

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Inbred Strains Mice
Ethanol
Air
Blood
Seizures
Inhalation Exposure
Genes
Vapors
Control Groups

Keywords

  • Alcoholism
  • Chronic Intermittent Ethanol Exposure
  • Convulsions
  • Ethanol Dependence and Withdrawal
  • Genetics
  • Inbred Mice

ASJC Scopus subject areas

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

Cite this

Withdrawal severity after chronic intermittent ethanol in inbred mouse strains. / Metten, Pamela; Sorensen, Michelle L.; Cameron, Andy J.; Yu, Chia Hua; Crabbe, John Jr.

In: Alcoholism: Clinical and Experimental Research, Vol. 34, No. 9, 09.2010, p. 1552-1564.

Research output: Contribution to journalArticle

Metten, Pamela ; Sorensen, Michelle L. ; Cameron, Andy J. ; Yu, Chia Hua ; Crabbe, John Jr. / Withdrawal severity after chronic intermittent ethanol in inbred mouse strains. In: Alcoholism: Clinical and Experimental Research. 2010 ; Vol. 34, No. 9. pp. 1552-1564.
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AB - Background: To study withdrawal, ethanol is usually administered chronically without interruption. However, interest has recurred in models of episodic exposure. Increasing evidence suggests that chronic intermittent exposure to ethanol leads to a sensitization effect in both withdrawal severity and ethanol consumption. The goal of the present study was to examine mouse inbred strain differences in withdrawal severity following chronic intermittent exposure using the handling-induced convulsion as the behavioral endpoint. We also sought to compare the withdrawal responses of inbred strains across acute, chronic continuous, and chronic intermittent exposure regimens. Methods: Male mice from 15 standard inbred strains were exposed to ethanol vapor for 16 hours each day for 3 days and removed to an air chamber during the intervening 8 hours. Mice in the control groups were handled the same, except that they were exposed only to air. Daily blood ethanol concentrations were averaged for each mouse to estimate total dose of ethanol experienced. Results: Across strains, mice had an average daily blood ethanol concentration (BEC) of 1.45 ± 0.02 mg/ml and we restricted the range of this value to 1.00-2.00 mg/ml. To evaluate strain differences, we divided data into two dose groups based on BEC, low dose (1.29 ± 0.1 mg/ml) and high dose (1.71 ± 0.02 mg/ml). After the third inhalation exposure, ethanol-exposed and air-exposed groups were tested hourly for handling-induced convulsions for 10 hour and at hour 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of air control values) in both dose groups. Conclusion: The chronic intermittent exposure paradigm is sufficient to elicit differential withdrawal responses across nearly all strains. Data from the high-dose groups correlated well with withdrawal data derived from prior acute (single high dose) and chronic continuous (for 72 hours) ethanol withdrawal studies, supporting the influence of common genes on all three responses.

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