The effect of treatment regimen on the development of tolerance to the sedative and anxiolytic effects of diazepam |
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Authors: | Cathy Fernandes Michelle I Arnot Elaine E Irvine Alan N Bateson Ian L Martin S E File |
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Institution: | (1) Psychopharmacology Research Unit, Neuroscience Research Centre, GKT School of Biomedical Sciences, King’s College London, London, UK, GB;(2) Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7, CA;(3) Division of Neuroscience, University of Alberta, Edmonton, Alberta, Canada T6G 2H7, CA;(4) Biological and Pharmaceutical Sciences, Aston University, Birmingham, UK, GB;(5) Psychopharmacology Research Unit, GKT School of Biomedical Sciences, Hodgkin Building, Guy’s Campus, London SE1 9RT, UK e-mail sandra.file@kcl.ac.uk Fax: +44-171-955-4627, GB |
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Abstract: | Rationale: Chronic treatment with benzodiazepines results in tolerance to their sedative and anxiolytic effects and there is considerable
evidence that different mechanisms underlie the development of tolerance to different behavioural 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 injections also provided a period of higher brain concentrations. Methods: Rats were tested in the holeboard, which provides measures of exploration and locomotor activity, and in the elevated plus-maze
and social interaction tests of anxiety. For those in the subcutaneous injection group the tests were 2 h after injection,
when brain concentrations were highest. Results: Despite a higher brain concentration in the injected group, both groups showed tolerance to diazepam’s sedative effects,
after 7 days of treatment. In contrast, in the elevated plus-maze, there was tolerance to the anxiolytic effects 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
could explain this result in the plus-maze, they cannot account for the pattern observed in the social interaction test, where
the injection group showed a significant anxiogenic effect at 28 days. Conclusions: Whereas the mechanism underlying tolerance to the sedative effects of diazepam was insensitive to the different treatment
regimens, the results suggest that different adaptive mechanisms were triggered in the two tests of anxiety with a differential
sensitivity to the treatment regimen. The adaptive mechanism predominating in the social interaction test was favoured by
the injection regimen which produced intermittent peak concentrations. This mechanism seems to be an oppositional one, leading
to an anxiogenic response, which was manifest despite high brain concentrations of diazepam at the time of testing.
Received: 12 July 1998 / Final version: 9 March 1999 |
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Keywords: | Benzodiazepine Tolerance Anxiety Sedation Exploration Motor activity |
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