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Repeated Cycles of Chronic Intermittent Ethanol Exposure Leads to the Development of Tolerance to Aversive Effects of Ethanol in C57BL/6J Mice

Authors

  • Marcelo F. Lopez,

    Corresponding author
    • Department of Psychiatry and Behavioral Sciences, Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, South Carolina
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  • William C. Griffin III,

    1. Department of Psychiatry and Behavioral Sciences, Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, South Carolina
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  • Roberto I. Melendez,

    1. School of Medicine, University of Puerto Rico, San Juan, Puerto Rico
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  • Howard C. Becker

    1. Department of Psychiatry and Behavioral Sciences, Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, South Carolina
    2. Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina
    3. Ralph H. Johnston Veterans Affairs Medical Center, Charleston, South Carolina
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Reprint requests: Marcelo F. Lopez, PhD, Department of Psychiatry and Behavioral Sciences, Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC 29425; Tel.: 843-789-6772; Fax: 843-792-5373; E-mail: lopezm@musc.edu

Abstract

Background

Repeated cycles of chronic intermittent ethanol (CIE) exposure lead to increased voluntary ethanol (EtOH) intake in C57BL/6J mice. This study evaluates the development of tolerance to EtOH's aversive effects in CIE exposure.

Methods

Adult male C57BL/6J mice were trained to drink 15% EtOH (vs. water) in a limited access procedure and then exposed to CIE (EtOH mice) or air (control [CTL] mice) for 5 cycles alternating with weekly access to EtOH drinking. Following the 4th CIE cycle, the aversive effects of EtOH were evaluated using a conditioned taste aversion (CTA) paradigm with 1% saccharin as the conditioned stimulus. Several doses of EtOH (0, 1, 2, and 3 g/kg) and LiCl (0.4 M, 0.02 ml/g) served as unconditioned stimuli. Finally, mice underwent a 5th CIE cycle to measure blood and brain concentrations following a 2 g/kg EtOH dose.

Results

CIE exposure increased EtOH drinking in EtOH mice while drinking in CTL mice remained stable. The lowest EtOH dose (1 g/kg) did not induce CTA in either group, but the highest dose (3 g/kg) produced CTA in both groups (49% reduction for CTL vs. 25% reduction for EtOH) although the group differences were not statistically significant. However, the 2 g/kg EtOH dose induced a significant aversion in CTL mice (27% reduction) but not in EtOH mice (20% increase), indicating tolerance to EtOH's aversive effects. LiCl caused a similar aversion in CTL and EtOH mice (50% reduction). Finally, blood and brain ethanol concentrations were not different between CTL and EtOH mice following a 2 g/kg EtOH dose.

Conclusions

The data indicate that CIE exposure produces tolerance to the aversive effects of 2 g/kg EtOH. This effect does not appear to be related to a learning deficit or altered EtOH pharmacokinetics. These data support the notion that tolerance to EtOH's aversive effects may contribute to excessive EtOH drinking in EtOH-dependent mice.

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