Exacerbation of Ethanol Withdrawal Seizures in Mice With a History of Multiple Withdrawal Experience

Abstract

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. We previously demonstrated that mice exposed to ethanol vapor for a total of 48 h exhibited more severe withdrawal seizures if the exposure was divided into three 16 h intoxication/8 h abstinence cycles than if the 48 h of exposure occurred in a single bout. The present study was designed to further characterize this model of ethanol withdrawal “kindling” and determine whether such a “kindled” response may be evident when withdrawal testing is conducted after an additional bout of intoxication that is the same for all groups. Adult C3H mice were chronically exposed to ethanol vapor in inhalation chambers for 40 h prior to withdrawal testing. Prior to this 40 h intoxication period, one group (Multiple Withdrawal; MW) received three cycles of 16 h ethanol vapor separated by 8 h abstinence; a second group (Single Withdrawal; SW) did not receive any ethanol exposure prior to the 40 h test cycle; a third group (Continuous Exposure; CE) received the same total ethanol exposure as the MW group (48 hr), but without interruption; and a control group (C) did not receive any ethanol treatment throughout the experiment. Blood ethanol levels following the 40 h bout of ethanol intoxication were 100–140 mg/dl for all ethanol-exposed groups. The severity of handling-induced convulsions during withdrawal was significantly greater in the MW group compared to CE and SW groups. These results suggest that differences in the severity of ethanol withdrawal seizures due to differences in prior withdrawal experience can be demonstrated even when later ethanol exposure patterns are equated. As such, the results provide further support for the “kindling” hypothesis of ethanol withdrawal.