Tolerance to the discriminative stimulus effects of ethanol following chronic inhalation exposure to ethanol in C57BL/6J mice

A significant consequence of chronic ethanol (EtOH) exposure is the development of tolerance. The present study was designed to investigate tolerance to the discriminative stimulus properties of EtOH following chronic EtOH exposure. Adult male C57BL/6J mice were trained to discriminate EtOH (1.00 g/kg; i.p.) from saline, using a food-reinforced two-lever operant task. Following acquisition and establishment of criterion discrimination performance, a series of generalization tests were conducted to generate a baseline EtOH dose-response curve with a calculated ED50 dose of 0.42 g/kg. Mice were then placed into control (air) or EtOH inhalation chambers for 64 h. In Experiment 1, discriminative stimulus generalization tests with the EtOH ED50 dose conducted 24 h following chronic EtOH (or air) exposure did not yield significantly different EtOH responding, although a trend towards reduced sensitivity to the EtOH cue (tolerance) was evident. In Experiment 2, a cumulative dosing procedure (ED50=0.37 g/kg) was employed, yielding a baseline EtOH dose-response function with a calculated ED50 dose of 0.37 g/kg. At 24 h following chronic EtOH exposure, re-determination of the EtOH dose-response curve revealed a significant shift to the right, with more than a twofold increase in the ED50 value (ED50=1.09 g/kg) compared to the control air exposure condition (ED50=0.49 g/kg). This apparent tolerance to the EtOH cue dissipated in chronic EtOH-exposed mice tested 48 h following the inhalation treatment (ED50=0.51 g/kg). These results demonstrate tolerance to the discriminative stimulus effects of EtOH in C57BL/6J mice following chronic EtOH exposure in inhalation chambers.