Tolerance and withdrawal after chronic lorazepam treatment in rats.
The purpose of the study was to develop an animal model for benzodiazepine tolerance and dependence on the basis of oral administration, using lorazepam as the test drug. We have used the continuous measurement of locomotor activity in home cages to obtain a narrow estimation of the time course of withdrawal related hyperactivity as an observer-independent symptom. Acute administration of lorazepam (9.5-37.5 mg/kg body weight/day) resulted in the first week in a dose-dependent muscle relaxation on the accelerod and sedation in the open field. The most striking manifestation of sedation, however, was the decrease of nocturnal locomotor activity in home cages. After 5 weeks of administration tolerance to the sedative effect had developed. In a second study, using a lower dose range (2.5-9.5 mg/kg body weight/day), a decrease of nocturnal locomotor activity was also observed as was the development of tolerance. The latter can be partly explained by dispositional tolerance, i.e., decreased serum concentrations after administration of lorazepam for more than 2 weeks. Withdrawal of lorazepam in the experiment using high doses led to three symptoms, i.e., a decrease in food intake, loss of body weight and an increase in daytime locomotor activity. The decrease in food intake and the loss of body weight were maximal on the first day of withdrawal. The increase in the daytime locomotor activity was present in the high dose experiment only, with a maximum on days 2-3 and a duration of at least 1 week. The increase however, was not dependent on the dose previously administered. The symptoms 'loss of body weight' and 'decrease in food intake' appeared to be more sensitive in benzodiazepine withdrawal: they were dose dependently present over the whole dosage range (2.5-37.5 mg/kg body weight/day). It is concluded that the model represents a sensitive model to measure lorazepam tolerance and dependence in animals. Comparative studies with other benzodiazepines are in progress.
van der Laan
J W
JW
Laboratory for Medicines and Medical Devices, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands.
Jansen van't Land
C
C
de Groot
G
G
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004361:Drug Tolerance; D004435:Eating / Q000187:drug effects; D008140:Lorazepam / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
D008140:Lorazepam