The effects of lorazepam discontinuation on responses to benzodiazepine agonists and antagonists were studied in mice.
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.
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.
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.
These data indicate a shift toward reduced agonist sensitivity and increased inverse agonist sensitivity in mice 4 days after lorazepam discontinuation.
Behavioral and neurochemical evidence indicates links between the opioid and GABA neurotransmitter systems. To assess effects of chronic opiates on the major site of postsynaptic GABAergic activity, the GABAA receptor, we administered chronic morphine and naltrexone to mice and evaluated binding at the benzodiazepine and t-butylbicyclophosphorothionate (TBPS) sites and GABA-dependent chloride uptake. After morphine (3 days), benzodiazepine receptor binding in vivo but not in vitro was increased in cortex compared to placebo-treated mice. TBPS binding was unchanged in cortex, but muscimol-stimulated chloride uptake was increased at low doses of muscimol. Benzodiazepine and TBPS binding and muscimol-stimulated chloride uptake were unchanged in naltrexone-(8 days) compared to placebo-treated mice. When naltrexone was administered previously to block opiate sites, the increases in benzodiazepine binding and chloride uptake observed with chronic morphine were reversed. These results indicate that chronic morphine but not naltrexone enhances benzodiazepine binding and GABAA receptor function, perhaps by an action at opioid receptors.
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