Aggressive and social behavior after alprazolam withdrawal: experimental therapy with Ro 19-8022
Introduction
Abrupt discontinuation of benzodiazepine treatment can increase anxiety and produce other signs of withdrawal such as insomnia, irritability and lowered seizure threshold in human or in animals [for review see 1, 2, 3, 4, 5].
The effects of benzodiazepines on aggression both in animals and human have been investigated extensively [for reviews see 6, 7, 8, 9], and the observation of taming activity of chlordiazepoxide in monkeys played an important role in the discovery of psychotropic activity of benzodiazepines [10]. Surprisingly, there is little information on changes of aggression during withdrawal from benzodiazepines. Virtually, no data have been published about the effects of benzodiazepine withdrawal on defensive–escape behavior occurring during social conflict which appears to be sensitive to drug effects on anxiety 11, 12.
Benzodiazepines can increase aggressive behavior at low doses in mice, rats and monkeys 9, 13, 14, 15, 16. Intermediate and higher doses of benzodiazepines reduce aggressive and defensive–escape activities and increase social investigatory behavior during intra species conflict in male laboratory mice 9, 11, 17, 18.
The aim of the present study was to determine whether withdrawal from alprazolam can increase anxiety-like and aggressive behavior during intra species conflict in mice and, if so, whether a quinolizinone derivate Ro 19-8022 ([R]-1-[(10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl)carbonyl]-2-pyrrolidine-methanol) with low abuse liability [19]which acts as a partial benzodiazepine receptor agonist is able to attenuate these behavioral changes without producing untoward effects such as sedation. An experimental model consisting of interactions of singly-housed male mice with non-aggressive group-housed male mice was used. In this ethologically-oriented laboratory model, analysis of offensive, defensive–escape, sociable, locomotor and other behavioral acts and postures enables evaluation of various putative motivational and emotional changes [12].
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Subjects
Male albino random-bred mice derived from ICR strain (Velaz, Prague) weighing 18–20 g at the beginning of the experimental housing were used. They were housed singly in self-cleaning cages or in groups of 10. The cages used for the individual housing were made of solid metal walls 13 cm high with wire-mesh floors (8×17 cm) which were placed 3 cm above trays with wood shavings. The isolates were not handled throughout the period of single housing. The mice kept in groups were housed in large
Behavior in the pre-withdrawal interaction
Mice treated with alprazolam (2 mg/kg/day) showed more social and less aggressive behavior than control animals (Table 1). Both the number and duration of social sniffing, climbing and following were significantly increased (the number of sniffs t=3.28, df=53, p=0.0018, the duration of sniffing t=2.72, df=53, p=0.088, the number of follows t=3.13, df=53, p=0.0028, the duration of sniffing t=2.67, df=53, p=0.0101, the number of climbs T=364, p=0.0123, the duration of climbing T=350, p=0.0059).
Discussion
In the present study, withdrawal from alprazolam was manifested by reduced social behavior and an increased aggression. These behavioral changes appear to be the opposite of acute effects of alprazolam, for which stimulation of social behavior and inhibition of aggression is characteristic in the present behavioral model 12, 18. In the present study, the high dose of alprazolam increased social behavior and reduced aggression also during repeated administration.
Although benzodiazepine
Acknowledgements
We would like to thank Mrs M. Likovská and Mrs L. Bartošová for their excellent technical assistance and Dr J. Martin and F. Hoffmann—La Roche Ltd for the gift of Ro 19-8022. Supported by the U.S.–Czech S. and T. Program, Project no. 93010, Grant Agency of Czech Republic (Project No. 309/96/0463), grant IGA 3612-3 from Czech Ministry of Health and a grant VS 96129 from Czech Ministry of Education.
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