Effect of duration and pattern of chronic ethanol exposure on tolerance to the discriminative stimulus effects of ethanol in C57BL/6J mice.

This study was conducted to examine whether amount and/or pattern (intermittent or continuous) of chronic ethanol exposure subsequently alters sensitivity to the discriminative stimulus effects of ethanol. Adult male C57BL/6J mice were trained to discriminate between 1.5 g/kg ethanol and saline in a two-lever food-reinforced operant procedure. Once ethanol discrimination was successfully acquired, generalization testing was conducted using a cumulative dosing procedure to generate a baseline dose-response function (0-2.5 g/kg ethanol). Discrimination training was then suspended while mice received chronic ethanol vapor or air exposure in inhalation chambers. The total amount of ethanol exposure was systematically increased, but it was delivered in an intermittent or continuous manner. At 24 or 16 h after inhalation treatment, ethanol discriminability was reassessed using the same generalization testing procedures. Results indicated that discrimination performance in control (air-exposed) mice was similar to baseline. However, sensitivity to the discriminative cue of ethanol following chronic ethanol treatment was reduced (as evidenced by rightward shifts in the dose-response functions and increased ED(50) values). The magnitude of this tolerance effect increased as a function of the number of chronic ethanol exposures as well as the total duration of ethanol exposure. In addition, tolerance was more robust when generalization testing was conducted earlier (16 versus 24 h) after chronic ethanol treatment was halted (2- to 3-fold increase in ED(50) values). These results may have important clinical implications, because blunted sensitivity to the discriminative cue of ethanol may contribute to enhanced ethanol self-administration behavior observed in these mice following similar chronic ethanol treatment.