title: Heightened aggression after chronic flunitrazepam in male rats: potential links to cortical and caudate-putamen-binding sites.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors: Laboratório de Neurociências, Centro 2, UNISINOS, Av. Unisinos, 950, 93022-000 São Leopoldo, RS, Brazil. rmalmeida@unisinos.br
authors: Rosa Maria M
authors: RM
authors: de Almeida
authors: Quelin
authors: Q
authors: Benini
authors: Juliana S
authors: JS
authors: Betat
authors: Débora C
authors: DC
authors: Hipólide
authors: Klaus A
authors: KA
authors: Miczek
authors: Anders I
authors: AI
authors: Svensson
mesh_terms: D000374:Aggression / Q000187:drug effects* / Q000523:psychology*; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005445:Flunitrazepam / Q000378:metabolism* / Q000494:pharmacology*; D018757:GABA Modulators / Q000378:metabolism* / Q000494:pharmacology*; D007206:Individuality; D008297:Male; D011699:Putamen / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018757:GABA Modulators; D011963:Receptors, GABA-A; D005445:Flunitrazepam