Lorazepam and MK-801 effects on behavioral and electrographic indices of alcohol withdrawal sensitization

Repeated cycles of chronic ethanol exposure and withdrawal result in sensitization of withdrawal-related CNS hyperexcitability that generally reflects an imbalance in activity of GABA and glutamate systems. Many pharmacological treatments for ethanol withdrawal target neuroadaptive changes in GABA and glutamate neurotransmission. The present study utilized a mouse model of repeated withdrawals to evaluate the ability of lorazepam and MK-801 treatments to antagonize behavioral and electroencephalographic (EEG) measures of sensitized withdrawal seizure activity. Adult male C3H/He mice received chronic intermittent ethanol vapor exposure in inhalation chambers (16 h/day) and during each withdrawal cycle, separate groups of mice were evaluated for handling-induced convulsions (HIC) or abnormal EEG (high-voltage "brief spindle episodes" (BSE)) activity. Lorazepam (0.5-1.0 mg/kg) or MK-801 (0.1-0.3 mg/kg) treatment at 1 h into each of three withdrawal cycles reduced behavioral (HIC) and electrographic (BSE) signs of seizure activity in a dose-related fashion compared to vehicle-treated mice. During a subsequent untreated withdrawal, mice previously treated with lorazepam or MK-801 for earlier withdrawals exhibited reduced HIC activity during the acute phase but exacerbated HIC activity during the protracted phase of this final (fourth) withdrawal cycle. Both lorazepam and MK-801 treatment conditions resulted in enhanced BSE activity during the entire fourth (untreated) withdrawal episode. Collectively, these results suggest that while treatment of repeated ethanol withdrawals with a benzodiazepine (lorazepam) or an NMDA receptor antagonist (MK-801) may have some initial benefits in ameliorating the development of sensitized withdrawal excitability, such treatment may also render subjects more vulnerable to seizure activity at later time points.