• Alcohol Dependence;
  • Alcohol Drinking;
  • Tolerance;
  • Learning;
  • Taste Aversion


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.


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.


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.


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.