No cross-tolerance between the stimulatory and depressant actions of benzodiazepines in mice.

Doses of the benzodiazepines chlordiazepoxide and diazepam were selected that elevate, or that depress, exploratory and locomotor behaviour in the holeboard in mice, and the development of tolerance to these effects was investigated. Tolerance did not develop to the stimulant effects of low doses of these compounds after 10 or 20 days pretreatment with either a low (stimulant) dose or a high (depressant) dose of each. When animals were pretreated with a high (depressant) dose of the benzodiazepines, tolerance developed to the depressant effects of a high test dose, and in fact, after 20 days a stimulatory effect on head-dipping had developed with this dose. In contrast, however, after pretreatment with a high (depressant) dose, there was no tolerance to the stimulatory effects of a low test dose of the benzodiazepines, even after 20 days. The ability of current theories is concluded that behavioural theories of tolerance, such as an instrumental conditioning model, may be the most appropriate to explain the present results.