Nielsen C K, Sánchez C
Pharmacological Research, H. Lundbeck A/S, Valby, Denmark.
Pharmacol Toxicol. 1995 Sep;77(3):177-81. doi: 10.1111/j.1600-0773.1995.tb01009.x.
Rats were tested in the footshock-induced ultrasonic vocalization model of anxiety. The ultrasounds were recorded 1-11 min after 10 inescapable 0.6 mA footshocks each of 1 sec. duration. Repeated administration of benzodiazepines in the clinic has been reported to be accompanied by development of tolerance and withdrawal anxiety. The present study examined whether the ultrasonic vocalization model could reflect these two side effects. Diazepam 4.6 or 8.8 mumol/ kg (1.3 or 2.5 mg/kg, subcutaneously) administered twice a day (8 a.m. and 4 p.m.) abolished the vocalization after acute administration and after 3 weeks of treatment. Hence, no tolerance developed to the anxiolytic effect of diazepam. When the rats were tested 24 and 48 hr after the last doses of diazepam there were no significant differences from the control group, i.e. no apparent withdrawal anxiety. Instead, the control groups developed tolerance to the shock regimen during the chronic experiments. This was examined further by daily testing of a group of naive rats for 13 days. The findings indicated that there is a limitation in number of test sessions before tolerance to the model develops. In conclusion, the results of the present study contribute to the many contradictory and by no mean unequivocally findings in the literature. It indicates that substantial prediction of anxiolytic effects as well as unwanted side effects cannot be made from one single test model.
