title: Tolerance liability of diazepam is dependent on the dose used for protracted treatment.
abstract: BACKGROUND
  Behavioral effects of benzodiazepines following repeated exposure vary according to the intrinsic efficacy of the benzodiazepine studied, treatment schedule and the behavioral parameters evaluated.
  
  
  METHODS
  We applied the behavioral paradigms of spontaneous locomotor activity, elevated plus maze and grip strength to investigate the sedative, anxiolytic and myorelaxant effect of acute challenge with 2 mg/kg diazepam administered after 14 days of protracted treatment with 0.5, 2 or 10 mg/kg of diazepam. In addition, we studied the effects of everyday handling and intraperitoneal (ip) administration on animal behavior.
  
  
  RESULTS
  Tolerance to the sedative effect of 2 mg/kg diazepam ensued after 14 days of protracted treatment with 2 and 10 mg/kg of diazepam. In contrast, treatment with the lowest dose (0.5 mg/kg) of diazepam resulted in potentiation of the sedative effect of acute challenge with 2 mg/kg diazepam thus confounding the detection of the anxiolytic effect of diazepam. Asensitization-like response to the anxiolytic action of 2 mg/kg diazepam was seen after protracted treatment with the intermediate dose (2 mg/kg); however, anxiolytic effect was absent after protracted administration of the highest dose. Partial tolerance to the muscle relaxant effect of 2 mg/kg diazepam ensued after protracted treatment with diazepam regardless of the dose. Daily handling or ip administration did not alter the behavioral response to acute challenge with 2 mg/kg diazepam in all the three behavioral paradigms studied.
  
  
  CONCLUSIONS
  The presented results showed that behavioral effects of acute challenge with diazepam were differently affected by the dose administered during protracted treatment.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia.
authors.forename: Jovana
authors.initials: J
authors.lastname: Divljaković
authors.forename: Marija
authors.initials: M
authors.lastname: Milić
authors.forename: Tamara
authors.initials: T
authors.lastname: Timić
authors.forename: Miroslav M
authors.initials: MM
authors.lastname: Savić
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D003975:Diazepam / Q000008:administration & dosage*; D004361:Drug Tolerance; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects
chemical_list: D014151:Anti-Anxiety Agents; D011963:Receptors, GABA-A; D003975:Diazepam