Functional tolerance to lorazepam in the rat.

The nature of the tolerance that develops to the sedative action of lorazepam was investigated using a hole-board apparatus. Rats treated with lorazepam (0.125, 0.25 and 0.50 mg/kg) once daily for 3 days showed similar degrees of tolerance to the effects of a test dose of 0.25 mg/kg lorazepam. Tolerance was also observed in animals treated once every 2 days with lorazepam (0.50 mg/kg). Measurement of the plasma and brain concentrations of lorazepam immediately after the behavioural test showed that this tolerance was functional and not dispositional. In contrast, the behavioural effects of lorazepam were not reduced as a result of 3 days of treatment with a sedative dose of sodium pentobarbitone (20 mg/kg), although this led to lower brain concentrations of lorazepam at the time of testing.