Alprazolam withdrawal and tolerance measured in the social conflict test in mice

Rationale: It is difficult to assess withdrawal from benzodiazepines, and p reclinical assessment of behaviour during social conflict offers the opport unity to quantify tolerance and withdrawal by measuring aggressive, defensi ve and social behaviour. The relationship between benzodiazepine withdrawal symptoms and the development of tolerance is not well understood. Are with drawal symptoms dependent on the development of tolerance? Objective: The a im of the present study was to compare the development of tolerance to alpr azolam effects on the behavioural repertoire during the social conflict tes t in mice, and to determine whether or not behavioural changes during alpra zolam withdrawal are correlated with the development of tolerance. Methods: An experimental model consisting of interactions of pairs of singly housed male mice with non-aggressive group-housed male mice was used. Alprazolam (1 mg/kg) was given orally once or repeatedly (twice daily) for 8 or 21 day s. Behaviour was measured, based on video-analysis, in aggressive mice befo re treatment, 30 min or 3 days after the last dose, respectively. Results: A single administration of alprazolam significantly reduced aggressive acti vities and increased social investigation without changing locomotion or ot her behaviour. Tolerance developed to the inhibitory effects of alprazolam on aggressive behaviour but not to the effects of alprazolam to increase so cial investigation. When withdrawn from alprazolam, mice exhibited less soc ial investigation and locomotion while aggression tended to be increased. C onclusions: Tolerance to the alprazolam effects on aggressive and social be haviour developed at different rates suggesting that they are differentiall y regulated. Furthermore, the evidence of withdrawal responses appearing in a behaviour to which tolerance had not developed does suggest that toleran ce and withdrawal phenomena are dissociated in benzodiazepines.