Lorazepam discontinuation promotes ‘inverse agonist’ effects of benzodiazepines

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Abstract
1 The effects of lorazepam discontinuation on responses to benzodiazepine agonists and antagonists were studied in mice. 2 The convulsant dose of pentylenetetrazol was decreased after an acute dose of lorazepam (0.5 mg kg−1) at 4 days after drug discontinuation, compared to 1 or 7 days after discontinuation or to vehicle treatment. 3 The percentage of mice undergoing convulsions after an acute dose of FG 7142 (40 mg kg−1) was increased at 4 days after lorazapam discontinuation, compared to 1 or 7 days after discontinuation or to vehicle treatment. 4 After an acute dose (0.5 mg kg−1), lorazepam concentrations in cortex tended to be greater in lorazepam-treated compared to vehicle-treated mice at 4 days after discontinuation compared to 1 and 7 days. 5 These data indicate a shift toward reduced agonist sensitivity and increased inverse agonist sensitivity in mice 4 days after lorazepam discontinuation.