Repeated Episodes of Ethanol Withdrawal Potentiate the Severity of Subsequent Withdrawal Seizures: An Animal Model of Alcohol Withdrawal “Kindling”

Prior experience with ethanol (EtOH) withdrawal may sensitize an individual to subsequent withdrawal episodes. It has been hypothesized that the progressive intensification of the EtOH withdrawal syndrome following repeated episodes of EtOH intoxication and withdrawal may represent the manifestations of a “kindling” mechanism. The purpose of this study was to develop an animal model of EtOH withdrawal that is sensitive to the effects of prior withdrawal experience. Adult male C3H mice were chronically exposed to EtOH vapor in inhalation chambers prior to withdrawal testing. A multiple withdrawal (MW) group received 3 cycles of 16 hr EtOH vapor separated by 8‐hr periods of abstinence; a single withdrawal (SW) group received a single bout of EtOH exposure (16 hr); a third group (SW‐CONT) experienced a single withdrawal episode after receiving the equivalent amount of EtOH intoxication as the MW group (16 × 3 = 48 hr), but in a continuous (uninterrupted) fashion; and a fourth group (C) served as controls, not receiving any EtOH exposure throughout the study. Severity of the withdrawal response was assessed by scoring handling‐induced convulsions hourly for the first 10 hr and then at 24 hr postwithdrawal. The results indicated that the severity of EtOH withdrawal seizures was significantly greater in animals that had a prior history of withdrawal episodes (MW group) in comparison to a separate group of animals that were tested following a single withdrawal from the same 16‐hr intoxication period (SW group). Moreover, the intensity of withdrawal seizures in MW animals was significantly greater than in animals exposed to an equivalent total amount of intoxication (48 hr), but only withdrawn a single time (SW‐CONT group). Differences in the severity of EtOH withdrawal seizures due to differences in prior withdrawal experience do not appear to be related to compromised health of the animals or to differences in the level of intoxication (blood EtOH levels) immediately preceding withdrawal assessment. As such, these results support the “kindling” hypothesis of EtOH withdrawal and provide a model with which to study potential mechanisms underlying the phenomenon.