Tolerance to and Dependence on Alprazolam are Due to Changes in GABAa Receptor Function and Are Independent of Exposure to Experimental Set-up

The development of tolerance to and dependence on BDZs was investigated by monitoring locomotor activity in mice. Alprazolam (6 mg/kg twice daily s.c.) or solvent were administered over 12 days. The treatment schedule at least 50% BDZ receptor occupancy throughout treatment. Receptor occupancy half-lives were determined to be 2.6 hrs and 4.8 hrs. after cessation of 4 and 12 days of alprazolam administration, respectively. To assess if the tolerance to and dependence on alprazolam were due to repeated exposure of mice to the experimental set-up, some groups of mice were tested repeatedly, while other groups were subjected only to a single exposure. The observed locomotor activity, measured as horizontal activity and total distance travelled, indicated that the development of tolerance and of withdrawal symptoms to alprazolam is not related to repeated exposure of the mice to the experimental set-up, but is due to changes in function of the GABAa receptor.