CHRONIC BENZODIAZEPINE ADMINISTRATION .12. ANTICONVULSANT CROSS-TOLERANCE BUT DISTINCT NEUROCHEMICAL EFFECTS OF ALPRAZOLAM AND LORAZEPAM

Tolerance to the sedative and anticonvulsant effects of benzodiazepines has been reported, but cross-tolerance among benzodiazepines is poorly characterized. To evaluate cross-tolerance between lorazepam and alprazolam in a reliable anticonvulsant pharmacodynamic model, we treated mice with either drug for 14 days, and with the two drugs sequentially for 7 days each. Pentylenetetrazole-induced seizure thresholds were similar in mice treated for 14 days with lorazepam or alprazolam, 2 mg/kg/day. For both compounds, a discontinuation effect characterized by reduced seizure threshold occurred at 4 days after discontinuation. Substitution of alprazolam for lorazepam after 1 week, and vice versa, did not interrupt tolerance. [H-3]flumazenil binding in vivo was downregulated in cortex after 14 days of either drug. However, binding was also reduced in hippocampus for lorazepam but not for alprazolam. Substitution of alprazolam for lorazepam resulted in downregulation in cortex only, similar to lorazepam alone. Conversely, substitution of lorazepam for alprazolam led to binding changes similar to lorazepam alone. These data demonstrate cross-tolerance to the convulsant effects of pentylenetetrazole between lorazepam and alprazolam. However, effects of the two compounds on benzodiazepine receptor binding in hippocampus remain distinct.