GABAA Receptor a Subunits Differentially Contribute to Diazepam Tolerance after Chronic Treatment

Background: Within the GABAA-receptor field, two important questions are what molecular mechanisms underlie benzodiazepine tolerance, and whether tolerance can be ascribed to certain GABAA-receptor subtypes. Methods: We investigated tolerance to acute anxiolytic, hypothermic and sedative effects of diazepam in mice exposed for 28-days to non-selective/selective GABAA-receptor positive allosteric modulators: diazepam (non-selective), bretazenil (partial non-selective), zolpidem (a1 selective) and TPA023 (a2/3 selective). In-vivo binding studies with [ 3H]flumazenil confirmed compounds occupied CNS GABAA receptors. Results: Chronic diazepam treatment resulted in tolerance to diazepam’s acute anxiolytic, hypothermic and sedative effects. In mice treated chronically with bretazenil, tolerance to diazepam’s anxiolytic and hypothermic, but not sedative, effects was seen. Chronic zolpidem treatment resulted in tolerance to diazepam’s hypothermic effect, but partial anxiolytic tolerance and no sedative tolerance. Chronic TPA023 treatment did not result in tolerance to diazepam’s hypothermic, anxiolytic or sedative effects. Conclusions: Our data indicate that: (i) GABAA-a2/a3 subtype selective drugs might not induce tolerance; (ii) in rodents quantitative and temporal variations in tolerance development occur dependent on the endpoint assessed, consistent wit