Repeated ethanol withdrawal experience increases the severity and duration of subsequent withdrawal seizures in mice

Repeated ethanol withdrawal experience has been shown to result in an exacerbation of future withdrawal episodes. This sensitization of the withdrawal response has been hypothesized to represent a “kindling” phenomenon. The present study was designed to examine whether a systematic increase in the number of previous ethanol withdrawal experiences increases both the severity and duration of a subsequent withdrawal response. An established model of repeated ethanol intoxication/withdrawal was employed in which adult C3H mice were chronically exposed to ethanol vapor in inhalation chambers. In the first experiment, multiple withdrawal (MW) groups of mice received nine (MW×9), six (MW×6), or three (MW×3) cycles of 16-h ethanol vapor separated by 8-h periods of abstinence prior to testing; a single withdrawal (SW) group was tested following a single bout of 16-h ethanol exposure; and a control (C) group did not receive any ethanol treatment throughout the experiment. In a second experiment, a group of mice (MW1–9) were repeatedly tested over nine cycles of withdrawal. A third experiment was designed to assess the effects of repeated pyrazole administration on the potentiated withdrawal seizure response. Results indicated a positive relationship between the number of previously experienced ethanol withdrawals and the severity and duration of a subsequent withdrawal episode. Blood ethanol levels were similar for all ethanol-exposed groups prior to withdrawal assessment. Further, the intensity of withdrawal seizures (handling-induced convulsions) progressively increased over nine cycles of intoxication/withdrawal and repeated testing did not significantly influence the development of this potentiated response. In addition, repeated administration of pyrazole did not appear to influence this withdrawal sensitization phenomenon. Collectively, these results provide further support for the “kindling” hypothesis of ethanol withdrawal.