Effects of Lorazepam Treatment for Multiple Ethanol Withdrawals in Mice

Abstract

Although many alcohol-dependent patients present with a history of prior detoxifications, the efficacy and safety of pharmacotherapy in the context of multiple ethanol withdrawal experiences have not been extensively studied. The purpose of this study was to evaluate the ability of lorazepam treatment for multiple withdrawals to prevent or blunt the development/expression of sensitized central nervous system hyperexcitability during a subsequent untreated withdrawal episode. A mouse model of withdrawal sensitization involving repeated ethanol withdrawals was used. Adult male C3H/He mice were exposed to different patterns of chronic ethanol vapor in inhalation chambers. One group received four cycles of 16 hr of ethanol exposure separated by 8-hr withdrawal periods, another group was tested after a single 16-hr exposure period, and a final group served as ethanol-naïve controls. These groups were further divided into lorazepam dosage (0.25-1.0 mg/kg) conditions. Lorazepam was administered 1 hr into each of the first three withdrawal cycles (or equivalent times); no drug injections were given during the final (fourth) withdrawal cycle. The ability of lorazepam treatment to alter development and expression of sensitized handling-induced convulsions (HIC), as well as changes in pentylenetetrazol seizure threshold dosage during an untreated withdrawal episode, was examined. Separate animals were used to assess the effects of lorazepam treatment on blood ethanol clearance and plasma levels of the benzodiazepine during the test withdrawal cycle. Lorazepam dose-dependently reduced HIC activity during successive withdrawal cycles, and this resulted in attenuated expression of the sensitized HIC response during the acute phase of a subsequent untreated withdrawal episode. However, HIC activity was exacerbated at later time points during this final test withdrawal in mice that had received lorazepam treatment for earlier withdrawals. A similar pattern of results was obtained for changes in pentylenetetrazol seizure threshold dosage. These results do not seem to be due to pharmacokinetic factors, because peak blood ethanol levels, rate of ethanol elimination, and plasma levels of lorazepam did not significantly differ among groups during the final test withdrawal cycle. Blocking central nervous system hyperexcitability during repeated ethanol withdrawals with lorazepam effectively blunts the development and expression of sensitized seizure activity during the acute phase of a subsequent unmedicated withdrawal episode. At later time points, withdrawal-related seizure activity was exacerbated, and this is possibly reflective of an interaction between protracted ethanol withdrawal and withdrawal from the benzodiazepine. The clinical implications of these findings suggest that repeated use of benzodiazepines for treatment of multiple ethanol withdrawals may have some initial beneficial effects, but such treatment may also place patients at increased risk of seizures at later time points.