Aggressive and social behavior after alprazolam withdrawal: experimental therapy with Ro 19-8022

https://doi.org/10.1016/S0149-7634(98)00017-7Get rights and content

Abstract

The aim of the present study was to ascertain whether withdrawal from alprazolam can increase anxiety-like and aggressive behavior during intra species conflict in mice and, if so, whether a partial benzodiazepine agonist Ro 19-8022 is able to reverse these behavioral changes without untoward effects such as sedation. 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 twice daily for 8 days and once on the 9th day. When withdrawn from alprazolam (3 days after the last dose), mice reduced social investigation and increased the incidence of aggressive behavior in comparison to the pre-withdrawal level. However, the increase of aggression was moderate and occurred only in subjects with low pre-treatment levels of aggression. Ro 19-8022 (10 mg/kg) significantly antagonized the decrease of social behavior and the increase of aggression after alprazolam withdrawal without causing sedation or ataxia.

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].

Section snippets

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.

References (37)

  • J.H Woods et al.

    Abuse liability of benzodiazepines

    Pharmacol. Rev.

    (1992)
  • Woods JH, Katz JL, Winger G. Abuse and therapeutic use of benzodiazepine-like drugs. In: Bloom FE, Kupfer DJ, editors....
  • Miczek KA. The psychopharmacology of aggression. In: Iversen LL, Iversen SD, Snyder SH, editors. Handbook of...
  • L.O Randall et al.

    The psychosedative properties of methaminodiazepoxide

    J. Pharmac. Exp. Ther.

    (1960)
  • M Kršiak

    Timid singly-housed mice: their value in prediction of psychotropic activity of drugs

    Br. J. Pharmacol.

    (1975)
  • Kršiak M, Šulcová A, Donát P, Tomašı́ková N, Kosar E, Mašek K. Can social and agonistic interactions be used to detect...
  • K.A Miczek

    Intraspecies aggression in rats: effects of d-amphetamine and chlordiazepoxide

    Psychopharmacologia

    (1974)
  • K.A Miczek et al.

    Alcohol and chlordiazepoxide increase suppressed aggression in mice

    Psychopharmacology

    (1980)
  • Cited by (16)

    • Acute and chronic glue sniffing effects and consequences of withdrawal on aggressive behavior

      2016, Life Sciences
      Citation Excerpt :

      The same trend was observed for both average distances between the two subjects and for the avoidance intensity (Fig. 3C–D). Socially stressed intruder animals are particularly interesting as models for human depression [28,29,30,31,32], while resident animals are often used as a model of human aggression [33]. Tests of aggressive behavior often referred to as resident–intruder or inter-male aggression tests [34,35] have become the most used protocol in animal studies of depression and aggression.

    • Sedative hypnotic abuse

      2007, xPharm: The Comprehensive Pharmacology Reference
    View all citing articles on Scopus
    View full text