The effect of treatment regimen on the development of tolerance to the sedative and anxiolytic effects of diazepam

Rationale: Chronic treatment with benzodiazepines results in tolerance to t heir sedative and anxiolytic effects and there is considerable evidence tha t different mechanisms underlie the development of tolerance to different b ehavioural effects. Objective: The purpose of the present experiment was to compare the behavioural effects of chronic treatment with diazepam (15 mg/ kg per day) given as daily subcutaneous injections or by osmotic minipump. Both regimens resulted in continual receptor occupancy, but the daily injec tions also provided a period of higher brain concentrations. Methods: Rats were tested in the holeboard, which provides measures of exploration and lo comotor activity, and in the elevated plus-maze and social interaction test s of anxiety. For those in the subcutaneous injection group the tests were 2 h after injection, when brain concentrations were highest. Results: Despi te a higher brain concentration in the injected group, both groups showed t olerance to diazepam's sedative effects, after 7 days of treatment. In cont rast, in the elevated plus-maze, there was tolerance to the anxiolytic effe cts in the pump group after 14, days, but a persisting anxiolytic effect in the injected group at 14 and 28 days. Whilst higher brain concentrations c ould explain this result in the plus-maze, they cannot account for the patt ern observed in the social interaction test, where the injection group show ed a significant anxiogenic effect at 28 days. Conclusions: Whereas the mec hanism underlying tolerance to the sedative effects of diazepam was insensi tive to the different treatment regimens, the results suggest that differen t adaptive mechanisms were triggered in the two tests of anxiety with a dif ferential sensitivity to the treatment regimen. The adaptive mechanism pred ominating in the social interaction test was favoured by the injection regi men which produced intermittent peak concentrations. This mechanism seems t o be an oppositional one, leading to an anxiogenic response, which was mani fest despite high brain concentrations of diazepam at the time of testing.