The anxiolytic action of benzodiazepines is not present in handling-habituated rats.

The acquisition of two-way shuttle avoidance (40 first trials) was used to test the anxiolytic activity of diazepam (2 and 4 mg/kg) and alprazolam (1.25 mg/kg) vs. vehicle, IP, in rats. These rats had received three different previous treatments: acute, acute with previous handling habituation for 15 days, and handling habituation combined with chronic treatment for 15 days. Results of the acute treatment showed a comparable anxiolytic action of diazepam and alprazolam, reflected by an improvement in avoidance acquisition. After handling habituation, no effect on shuttle box acquisition was obtained in rats acutely treated with diazepam, whereas the alprazolam-treated group showed a significantly impaired avoidance performance. When handling habituation was combined with chronic benzodiazepine treatment, the drugs' anxiolytic action persisted although there was a complete disappearance of their sedative effects. These behavioral results are discussed in relation to the emotional changes induced by the procedures of handling. They are tentatively linked with possible changes in the functionality of GABA neurotransmission, possibly at the level of the GABA-benzodiazepine receptor which some studies have found associated to handling habituation.