While respiratory alkalosis has been reported to occur in human alcoholics during the withdrawal period, and may causally contribute to the expression of the withdrawal syndrome, we found no evidence of this in either alcohol physically-dependent mice (DBA/2J) or rats (Sprague-Dawley) as reflected in blood pH, plasma pCO 2, or intracellular brain pH relative to pair-fed control (no alcohol) animals. The inhalation of atmospheres high in CO 2 (5% and 15%), which would be expected to reverse a respiratory alkalotic state, had no effect on the expression of the withdrawal syndrome in alcohol-dependent mice. These results indicate that a withdrawal syndrome of considerable intensity can develop in mice and rats in the absence of an alkalotic state.