PHYSICAL-DEPENDENCE ON DIAZEPAM AND LORAZEPAM IN THE DOG

  • 1 January 1983
    • journal article
    • research article
    • Vol. 226  (3) , 783-789
Abstract
Dogs, surgically implanted with a gastric fistula, were chronically dosed with diazepam or lorazepam. Diazepam (60 mg/kg per day) or lorazepam (100 mg/kg per day) was administered intragastrically in 4 divided daily doses. Beginning no less than 2 wk after the attainment of stabilization doses, dogs underwent withdrawal experiments, repeated at 2-wk intervals. At a time of withdrawal determined by a Latin square crossover design, dogs were observed for 8 h for signs of abstinence. Both diazepam and lorazepam caused a withdrawal abstinence syndrome to appear upon abrupt discontinuation of the drug. The 2 abstinence syndromes had many signs in common, including tremor, hot foot walking, rigidity and decreased food intake; the lorazepam withdrawal abstinence syndrome was much less intense and had a shorter latency to onset than the diazepam abstinence syndrome, which also included clonic and tonic-clonic convulsions and was lethal in 2 dogs. The diazepam withdrawal abstinence syndrome was biphasic, the 1st phase apparent by 24 h and a 2nd phase beginning at 48 h, while the lorazepam syndrome was not. Diazepam suppressed the major signs of diazepam abstinence in a dose-related manner, but failed to completely suppress all signs of abstinence. CGS-8216 [2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one], a pyrazoloquinoline benzodiazepine antagonist, precipitated abstinence in the diazepam-dependent dog, but did not precipitate tonic-clonic seizures. No abstinence syndrome was precipitated in the lorazepam-dependent dog. Apparently, while diazepam and lorazepam both cause physical dependence the 2 syndromes are not the same. Physical dependence on and withdrawal from diazepam involves at least 2 separate mechanisms with different selectivity for benzodiazepine agonists and antagonists.