Lack of cross-tolerance in mice between the stimulatory and depressant actions of novel anxiolytics in the holeboard.

CL 218,872, tracazolate and tofisopam are compounds that are believed to act at the GABA-benzodiazepine (BDZ) receptor complex in the CNS and that have anxiolytic properties in animals or in man. Doses of each drug were selected to elevate, or to depress, exploratory head-dipping and locomotor activity in the holeboard in mice, and the development of tolerance to these effects was investigated. As previously found with benzodiazepines, tolerance did not develop to the stimulant effects of low doses of these compounds after 10 days pretreatment with either a low (stimulant) or a high (depressant) dose of the same compound. When animals were pretreated with a low (stimulant) dose, tolerance did not develop to the depressant effects of a high test dose. Tolerance was observed only to the depressant effects of a high dose of a drug, and only when animals were also pretreated with a high dose. The results are compared with those obtained with benzodiazepines, and the ability of current theories of tolerance to account for the results is discussed.