REPEATED ETHANOL WITHDRAWAL EXPERIENCE SELECTIVELY ALTERS SENSITIVITYTO DIFFERENT CHEMOCONVULSANT DRUGS IN MICE

Repeated ethanol withdrawal experience has been shown to result in exa cerbated seizures associated with future withdrawal episodes. This sen sitization of the withdrawal response has been postulated to represent a ''kindling'' phenomenon. The present study employed an established model of repeated ethanol withdrawals to examine the potential role of GABA,, and NMDA and non-NMDA glutamate receptor systems in mediating enhanced seizure activity, as assessed by sensitivity to seizures indu ced by pentylenetetrazol (PTZ), NMDA, and kainic acid (KA) IV infusion s, respectively. Adult C3H mice were chronically exposed to ethanol va por in inhalation chambers. A multiple withdrawal (MW) group received four cycles of 16-h ethanol vapor exposure interrupted by 8-h periods of abstinence; a single withdrawal (SW) group was tested after a singl e 16-h bout of ethanol intoxication; and the third group was ethanol-n aive, serving as controls (C). Results indicated that the MW group evi denced significantly lower PTZ and NMDA seizure thresholds compared to SW and C groups at 8 and 24 h post-withdrawal. In contrast, MW and SW groups exhibited reduced sensitivity (higher seizure threshold) to KA in comparison to controls, and this effect only emerged at 24 h post- withdrawal. Further, MW mice required significantly less additional PT Z or NMDA to induce more severe convulsions once initial signs of seiz ures were elicited. Conversely, latency and amount of KA required to t ransition from initial seizure signs to more severe end-stage convulsi ons was significantly greater for MW and SW groups compared to control s. Taken together, these results suggest that repeated ethanol withdra wal experience does not result in a global non-specific lowering of th reshold to convulsive stimuli, but rather, selective changes in CNS me chanisms associated with neural excitability may underlie potentiated withdrawal responses. Thus, reduced GABAA receptor function and increa sed NMDA receptor activity may become exaggerated as a consequence of repeated withdrawal experience, while reduced sensitivity to KA induce d seizures may represent a compensatory response to withdrawal-related CNS hyperexcitability.