Benzodiazepine--specific and nonspecific tolerance following chronic flurazepam treatment.

Rats were given a flurazepam solution as their only water source for 4 weeks. The drug concentration was adjusted so the rats would consume 100-150 mg/kg daily. This treatment is known to cause a reduction in the number of specific benzodiazepine binding sites (receptor down-regulation) and tolerance to the locomotor impairment caused by the injection of a large test dose of flurazepam. Both the tolerance and the receptor down-regulation disappear within 24 hours after the end of chronic treatment. After 4 weeks of flurazepam treatment, rats were tested for locomotor impairment and loss of the righting response caused by pentobarbital, ethanol or diazepam. There was a small tolerance to pentobarbital. This lasted at least 4 days, but had disappeared by 7 days. Rats also had a small tolerance to ethanol, which disappeared between 24 and 48 hours after the end of chronic flurazepam treatment. In contrast, there was a large tolerance to diazepam, but this was gone by 24 hours after the end of chronic treatment. It appears that two types of tolerance develop during benzodiazepine treatment: (1) tolerance specific for benzodiazepines possibly mediated by receptor down-regulation, and (2) nonspecific tolerance, possibly analogous to that which develops during chronic barbiturate treatment.