Heightened aggression after chronic flunitrazepam in male rats: potential links to cortical and caudate-putamen-binding sites

Heightened aggression after chronic flunitrazepam in male rats: potential links to cortical and caudate-putamen-binding sites

Author Almeida, Rosa Maria M. de Google Scholar
Benini, Quelin Google Scholar
Betat, Juliana S. Google Scholar
Hipolide, Debora C. Autor UNIFESP Google Scholar
Miczek, Klaus A. Google Scholar
Svensson, Anders I. Google Scholar
Institution Univ Vale Rio dos Sinos
Universidade Federal de São Paulo (UNIFESP)
Tufts Univ
Univ Gothenburg
Abstract Rationale Higher doses of benzodiazepines induce sedation. However, in low to moderate doses, benzodiazepines can increase aggressive behavior both after acute and chronic administration. the determinants for increasing aggression after chronic intake of flunitrazepam, a so-called date rape drug, in violence-prone individuals are incompletely understood.Objectives the aim of this study is to assess the effects of acute and chronic treatment with flunitrazepam on male aggression in resident rats. We also examined possible changes in binding to benzodiazepine receptors throughout the brain of rats that display aggressive behavior after repeated flunitrazepam treatment using quantitative receptor autoradiography.Materials and methods the behaviors of the male Wistar resident rats (n=35) toward a male intruder were recorded for 10 min twice a week. the salient aggressive and non-aggressive elements in the resident rat's behavior were analyzed. Initially, the dose-dependent effects of flunitrazepam (0.01, 0.03, 0.1, 0.18, and 0.3 mg/kg) or vehicle were determined in all rats; subsequently, 0.3 mg/kg per day flunitrazepam was administered for 42 days (n=15), and a parallel group was treated with vehicle (n=20). After the chronic treatment, the flunitrazepam (0, 0.01, 0.03, 0.1, 0.18, and 0.3 mg/kg) effects were again assessed.Results the most significant finding is the escalation of aggression after chronic treatment with flunitrazepam. A previously sedative 0.3 mg/kg dose of flunitrazepam engendered very high levels of attack bites, sideways threats, and aggressive postures (total aggression) after 6 weeks of daily administration. Individual differences emerged, and these were associated with decreased binding to benzodiazepine receptors, mainly in the limbic structures such as the cingulate cortex (cingulate areas 1 and 2) and caudate-putamen (posterior part) of aggressive animals, suggesting that these areas are pivotal in the control of emotional and aggressive behavior.Conclusions Chronic flunitrazepam produces changes in receptor binding in discrete areas of the cingulate cortex and caudate-putamen that are proposed to be part of the mechanisms for increased expression of aggressive behavior.
Keywords aggression
GABA(A) receptor
cingulate cortex
Language English
Date 2008-04-01
Published in Psychopharmacology. New York: Springer, v. 197, n. 2, p. 309-318, 2008.
ISSN 0033-3158 (Sherpa/Romeo, impact factor)
Publisher Springer
Extent 309-318
Origin http://dx.doi.org/10.1007/s00213-007-1031-5
Access rights Closed access
Type Article
Web of Science ID WOS:000254205600011
URI http://repositorio.unifesp.br/handle/11600/30550

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