title: Physical dependence after benzodiazepine treatments in rats: Comparison of short and long treatments with diazepam and lorazepam.
abstract: OBJECTIVE
  This study examined the development of physical dependence after different durations of treatments with two benzodiazepines (diazepam and lorazepam).
  
  
  METHODS
  Increased excitation in the central nervous system during a 2-week withdrawal period after 4-day and 4-week treatments with diazepam and lorazepam was examined with an EEG threshold method in male rats. Increased excitation was measured as a decreased sensitivity to hexobarbital (i.e., increased threshold doses). The concentrations of hexobarbital in two different brain regions, serum, fat and muscle tissue after 4-week treatment with diazepam were determined with a high-pressure liquid chromatography method.
  
  
  RESULTS
  The duration of withdrawal was influenced by the duration of treatment but the maximum level of withdrawal excitation was similar for both drugs. Equieffective doses of diazepam (20 mg/kg) and lorazepam (2 mg/kg) induced similar patterns of withdrawal excitability after both treatments. The brain concentrations of hexobarbital were significantly higher on Days 1 and 3 of withdrawal after diazepam treatment. Significant correlations between the threshold doses and brain concentrations were found on Day 1, but these correlations disappeared on day 3. At the same time, a difference between the concentrations of hexobarbital in different brain areas emerged.
  
  
  CONCLUSIONS
  The duration of treatment had a minor influence on the pattern of withdrawal excitation. Equieffective doses of diazepam and lorazepam induced comparable withdrawal excitability indicating no significant difference in their potential to induce physical dependence. The time-dependent change in the hexobarbital concentrations in the brain suggests that withdrawal excitation after diazepam treatment is a complex phenomenon probably involving several different systems at different times.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Umeå University, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Korkmaz
authors.forename: G
authors.initials: G
authors.lastname: Wahlström
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000633:toxicity; D001143:Arousal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004569:Electroencephalography / Q000187:drug effects; D006591:Hexobarbital / Q000493:pharmacokinetics; D008140:Lorazepam / Q000633:toxicity; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000209:etiology; D019966:Substance-Related Disorders / Q000523:psychology*; D014018:Tissue Distribution
chemical_list: D014151:Anti-Anxiety Agents; D006591:Hexobarbital; D008140:Lorazepam; D003975:Diazepam