Positive relationship between the number of prior ethanol withdrawal episodes and the severity of subsequent withdrawal seizures.

One factor that has been shown to influence the severity of an ethanol withdrawal syndrome is a history of prior experience with episodes of ethanol withdrawal. It has been hypothesized that the progressive intensification of withdrawal symptoms following repeated bouts of ethanol intoxication and withdrawal may represent the manifestations of a "kindling-like" process. In mice, repeated episodes of ethanol withdrawal potentiate the severity of subsequent withdrawal seizures, even when the total amount of ethanol intoxication is equated across groups. In the current experiments, mice received 16-h bouts of continuous exposure to ethanol vapor in inhalation chambers separated by 8-h periods of abstinence. The withdrawal response was assessed by scoring handling-induced convulsions. The results demonstrated that a positive relationship exists between the number of prior episodes of ethanol withdrawal and the severity of subsequent withdrawal seizures. This conclusion was supported by both between-subject and within-subject comparisons. The difference in withdrawal severity does not appear to be related to differences in the level of intoxication, since blood ethanol levels immediately preceding withdrawal testing were similar for all groups. Further, the differential withdrawal response exhibited by multiple and single withdrawal groups cannot be explained by a difference in the rate of ethanol elimination. Although the mechanism(s) remain to be determined, taken together, these results provide support for the "kindling" hypothesis of ethanol withdrawal.