P Rats Develop Physical Dependence on Alcohol Via Voluntary Drinking: Changes in Seizure Thresholds, Anxiety, and Patterns of Alcohol Drinking

Authors

  • Alexey B. Kampov-Polevoy,

    1. From the Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
    2. Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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  • Douglas B. Matthews,

    1. From the Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
    2. Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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  • Lee Gause,

    1. From the Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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  • A. Leslie Morrow,

    1. From the Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
    2. Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
    3. Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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  • David H. Overstreet

    Corresponding author
    1. From the Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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  • The study was supported by P50 AA11605 and NRSA AA05519 grants from NIAAA. The P rats obtained from the Indiana Alcohol Research Center were supported by P50-AA07611 from NIAAA.

Reprint requests: David H. Overstreet, Ph.D., Bowles Center for Alcohol Studies, CB#7178, 3011 Thurston-Bowles Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178; Fax: 919-966-5679.

Abstract

Background: It has been proposed that the alcohol-preferring P rat meets many of the criteria for an animal model of alcoholism. However, the development of alcohol dependence has not been explored in rats that self-administer ethanol for less than 15–20 weeks. The present study investigated the development of physical dependence upon alcohol after 2–6 weeks of voluntary alcohol intake. Changes in bicuculline-induced seizure thresholds, microstructure of alcohol drinking, and anxiety-related behavior were used as indices of alcohol dependence. In addition, we evaluated the microstructure of alcohol drinking associated with the development of physical dependence upon alcohol.

Methods: Alcohol (10% ethanol solution) was measured in graduated drinking tubes with both alcohol and water available continuously. Microstructure of alcohol intake was monitored by a computerized drinkometer. Physical dependence upon alcohol was determined by measuring bicuculline-induced seizure thresholds after alcohol withdrawal. Anxiety-related behavior of P rats after alcohol withdrawal was determined by the social interaction and elevated plus maze tests.

Results: Initial alcohol intake in the alcohol-preferring P rat was relatively modest (3.9 ± 0.4 g/kg/day). Four days of forced alcohol exposure (initiation) followed by 6 weeks of voluntary drinking resulted in an increase of alcohol intake to 5.5 ± 0.2 g/kg/day. Ethanol self-administration for 6 weeks, but not for 2 or 4 weeks, produced a significant reduction (30%; p < 0.05) in bicuculline-induced seizure thresholds during alcohol withdrawal. Alterations in the microstructure of alcohol intake (i.e., 90% increase in the size of alcohol drinking bouts compared to the baseline [p < 0.001] with no change in bout frequency) were associated with the development of alcohol dependence. Termination of alcohol intake after 6 weeks of voluntary alcohol consumption resulted in increased anxiety according to both the social interaction and elevated plus maze tests.

Conclusions: The results of this study indicate that 6 weeks of voluntary alcohol intake are sufficient for the development of physical dependence upon alcohol in the alcohol-preferring P rats as measured by susceptibility to bicuculline-induced seizures. This time is much shorter than the 15–20 weeks reported earlier. Development of physical dependence to alcohol was associated with an increase in daily alcohol intake (40% over the baseline), an increase in alcohol intake during each drinking bout (90% over the baseline), and elevated anxiety during alcohol withdrawal.

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