Skip to main content
SpringerLink
Log in

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

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Apfelbach R, Delgado J (1974) Social hierarchy in monkeys (Macaca mulatta) modified by chlordiazepoxide hydrochloride. Neuropharmacol 13:11–20

    Article  CAS  Google Scholar 

  • Azevedo A, Alóe F, Hasan R (2004) Hipnóticos. Rev Neurocienc 12:29–39

    Google Scholar 

  • Ben-Porath D, Taylor S (2002) The effects of diazepam (valium) and aggressive disposition on human aggression: an experimental investigation. Addict Behav 27:167–77

    Article  PubMed  Google Scholar 

  • Benazzi F, Mazzoli M, Rossi E (1993) A study of intramuscular clonazepam for psychotic agitation (letter). Can J Psychiatry 38:70–71

    PubMed  CAS  Google Scholar 

  • Blair R (2004) The roles of orbital frontal cortex in the modulation of antisocial behavior. Brain Cogn 55:198–208

    Article  PubMed  CAS  Google Scholar 

  • Bond A, Curran H, Bruce M, O’Sullivan G, Shine P (1995) Behavioural aggression in panic disorder after 8 weeks’ treatment with alprazolam. J Affect Disord 35:117–123

    Article  PubMed  CAS  Google Scholar 

  • Bradwejn J, Shriqui C, Koszycki D, Meterissian G (1990) Doubleblind comparison of the effects of clonazepam and lorazepam in acute mania. J Clin Psychopharmacol 10:403–408

    Article  PubMed  CAS  Google Scholar 

  • Chouinard G, Annable L, Turnier L, Holobow N, Szkrumelak N (1993) A double blind randomized clinical trial of rapid tranquilization with I. M. Clonazepam and I. M. Haloperidol in agitated psychotic patients with manic symptoms. Can J Psychiatry 38:S114–S121

    PubMed  Google Scholar 

  • Cook L, Sepinwall J (1975) Behavior analysis of the effects and mechanisms of action of benzodiazepines. Psychopharmacol Bull 11:53–55

    PubMed  CAS  Google Scholar 

  • Cowdry R, Gardner D (1988) Pharmacotherapy of borderline personality disorder. Alprazolam, carbamazepine, trifluoperazine, and tranylcypromine. Arch Gen Psychiatry 45:111–119

    PubMed  CAS  Google Scholar 

  • Cox ED, Hagen TJ, McKernan RM, Cook JM (1995) BZ1 receptor subtype specific ligands: synthesis and biological properties of β-CCt, a BZ1 receptor subtype specific antagonist. Med Chem Res 5:710–718

    CAS  Google Scholar 

  • Dåderman A (2000) Flunitrazepam and violence—psychiatric and legal issues Karolinska Institute. Huddinge, Sweden

    Google Scholar 

  • Davidson RJ, Putnam KM, Larson CL (2000) Dysfunction in the neural circuitry of emotion regulation–a possible prelude to violence. Science 289:591–594

    Article  PubMed  CAS  Google Scholar 

  • de Almeida RMM, Rowlett JK, Cook JM, Yin W, Miczek KA (2004) GABAA/alpha1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice. Psychopharmacol (Berl) 172:255–263

    Article  CAS  Google Scholar 

  • DiMascio A (1973) The effects of benzodiazepines on aggression: reduced or increased. Psychopharmacol 30:95–102

    Article  CAS  Google Scholar 

  • Dubiela F, de Oliveira M, Moreira K, Nobrega J, Tufik S, Hipolide D (2005) Learning deficits induced by sleep deprivation and recovery are not associated with altered [(3)H]muscimol and [(3)H]flunitrazepam binding. Brain Res 1037:157–163

    Article  PubMed  CAS  Google Scholar 

  • Fernandes C, File S, Berry D (1996) Evidence against oppositional and pharmacokinetic mechanisms of tolerance to diazepam’s sedative effects. Brain Res 734:236–242

    Article  PubMed  CAS  Google Scholar 

  • File SE (1980) The use of social-interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J Neurosci Meth 2(3):219–238

    Article  CAS  Google Scholar 

  • File S, Pellow S (1990) Psychotropic drugs of abuse. Pergamon, New York

    Google Scholar 

  • Foster S, Kessel J, Berman M, Simpson G (1997) Efficacy of lorazepam and haloperidol for rapid tranquillisation in a psychiatric emergency room setting. Int Clin Psychopharmacol 12:175–179

    Article  PubMed  CAS  Google Scholar 

  • Fox K, Snyder R (1969) Effect of sustained low doses of diazepam on aggression and mortality in grouped male mice. J Comp Physiol Psychol 69:663–666

    Article  PubMed  CAS  Google Scholar 

  • Gardner CR, Piper DC (1982) Effects of agents which enhance GABA-mediated neurotransmission on licking conflict in rats and exploration in mice. Eur J Pharmacol 83:25–33

    Article  PubMed  CAS  Google Scholar 

  • Gardner DL, Cowdry RW (1985) Alprazolam-induced dycontrol in borderline personality disorder. Am J Psychiatry 142(1):98–100

    PubMed  CAS  Google Scholar 

  • Gourley S, Debold J, Yin W, Cook J, Miczek K (2005) Benzodiazepines and heightened aggressive behavior in rats: reduction by GABA(A)/alpha(1) receptor antagonists. Psychopharmacol (Berl) 178:232–40

    Article  CAS  Google Scholar 

  • Hentschke H, Schwarz C, Antkowiak B (2005) Neocortex is the major target of sedative concentrations of volatile anaesthetics: strong depression of firing rates and increase of GABAA receptor-mediated inhibition. Eur J Neurosci 21:93–102

    Article  PubMed  Google Scholar 

  • Huang Q, He X, Ma C, Liu R, Yu S, Dayer CA, Wenger GR, McKernan R, Cook JM (2000) Pharmacophore/receptor models for GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) via a comprehensive ligand-mapping approach. J Med Chem 43:71–95

    Article  PubMed  CAS  Google Scholar 

  • Hutchinson M, Smith P, Darlington C (1996) The behavioural and neuronal effects of the chronic administration of benzodiazepine anxiolytic and hypnotic drugs. Prog Neurobiol 49:73–97

    PubMed  CAS  Google Scholar 

  • Irvine EE, Cheeta S, Lovelock C, File SE (2001) Tolerance to midazolam’s anxiolytic effects after short-term nicotine treatment. Neuropharmacol 40:710–716

    Article  CAS  Google Scholar 

  • Jackson A, Koek W, Colpaert FC (1995) Can the DRL 72s schedule selectively reveal antidepressant drug activity? Psychopharmacology (Berl) 117:154–161

    Article  CAS  Google Scholar 

  • Krsiak M (1979) Effects of drugs on behaviour of aggressive mice. Br J Pharmacol 65:525–533

    PubMed  CAS  Google Scholar 

  • Lader M (1989) Benzodiazepines in profile. Prescr J 29:12–18

    Google Scholar 

  • Lader M (1999) Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified? Eur Neuropsychopharmacol 9(Suppl 6):S399–S405

    Article  PubMed  CAS  Google Scholar 

  • LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184

    Article  PubMed  CAS  Google Scholar 

  • Lion J (1979) Benzodiazepines in the treatment of aggressive patients. J Clin Psychiatry 40:70–71

    PubMed  CAS  Google Scholar 

  • Low K, Crestani F, Keist R, Benke D, Brunig I, Benson JA, Fritschy JM, Rulicke T, Bluethmann H, Mohler H, Rudolph U (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290:131–134

    Article  PubMed  CAS  Google Scholar 

  • Lucchesi L, Pompeia S, Manzano G, Kohn A, Galduroz J, Bueno O, Tufik S (2003) Flunitrazepam-induced changes in neurophysiological, behavioural, and subjective measures used to assess sedation. Prog Neuropsychopharmacol Biol Psychiatry 27:525–533

    Article  PubMed  CAS  Google Scholar 

  • Maclean PD (1954) The limbic system and its hippocampal formation; studies in animals and their possible application to man. J Neurosurg 11:29–44

    PubMed  CAS  Google Scholar 

  • MacLean PD (1990) The triune brain in evolution: Role in paleocerebral functions. Plenum, New York

    Google Scholar 

  • McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha(1) subtype. Nature Neurosc 3(6):587–592

    Article  CAS  Google Scholar 

  • Miczek K (1974) Intraspecies aggression in rats: effects of d-amphetamine and chlordiazepoxide. Psychopharmacology 39:275–301

    Article  CAS  Google Scholar 

  • Miczek K, O’Donnell J (1980) Alcohol and chlordiazepoxide increase suppressed aggression in mice. Psychopharmacol (Berl) 69:39–44

    Article  CAS  Google Scholar 

  • Miczek KA, de Boer SF (2005) Aggressive, defensive and submissive behavior. In: Wishaw IQ, Kolb B (eds) The behavior of the laboratory rat: a handbook with tests. Oxford University Press, Oxford, pp 344–352

    Google Scholar 

  • Miczek KA, Fish EW (2006) Monoamines, GABA, glutamate and aggression. In: Nelson RJ (ed) Biology of aggression. Oxford University Press, Oxford, pp 114–149

    Google Scholar 

  • Miczek K, Fish E, De Bold J (2003) Neurosteroids, GABAA receptors, and escalated aggressive behavior. Horm Behav 44:242–257

    Article  PubMed  CAS  Google Scholar 

  • Morgane PJ, Galler JR, Mokler DJ (2005) A review of systems and networks of the limbic forebrain/limbic midbrain. Prog Neurobiol 75:143–160

    Article  PubMed  Google Scholar 

  • O’Sullivan G, Noshirvani H, Basoglu M, Marks I, Swinson R, Kuch K, Kirby M (1994) Safety and side-effects of alprazolam. Controlled study in agoraphobia with panic disorder. Br J Psychiatr 165:79–86

    CAS  Google Scholar 

  • Olivier B, Mos J, van Oorschot R (1985) Maternal aggression in rats: effects of chlordiazepoxide and fluprazine. Psychopharmacology (Berl) 86:68–76

    Article  CAS  Google Scholar 

  • Olivier B, Mos J, Miczek K (1991) Ethopharmacological studies of anxiolytics and aggression. Eur Neuropsychopharmacol 1:97–100

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The brain in stereotaxic coordinates. 4th edition, Academic Press

  • Pritchett DB, Sontheimer H, Shivers BD, Ymer S, Kettenmann H, Schofield PR, Seeburg PH (1989) Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature 338:582–585

    Article  PubMed  CAS  Google Scholar 

  • Rodgers R, Waters A (1985) Benzodiazepines and their antagonists: a pharmacoethological analysis with particular reference to effects on “aggression”. Neurosci Biobehav Rev 9:21–35

    Article  PubMed  CAS  Google Scholar 

  • Rowlett JK, Platt DM, Lelas S, Atack JR, Dawson GR (2005) Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates. Proc Natl Acad Sci USA 102:915–920

    Article  PubMed  CAS  Google Scholar 

  • Rudolph U, M, hler H (2006) GABA-based therapeutic approaches: GABA(A) receptor subtype functions. Curr Opin Pharmacol 6(1):18–23

    Article  PubMed  CAS  Google Scholar 

  • Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Möhler H (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401:796–800

    Article  PubMed  CAS  Google Scholar 

  • Rudolph U, Crestani F, M, hler H (2001) GABA(A) receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol Sci 22:188–194

    Article  PubMed  CAS  Google Scholar 

  • Siegel A, Roeling T, Gregg T, Kruk M (1999) Neuropharmacology of brain-stimulation-evoked aggression. Neurosci Biobehav Rev 23:359–389

    Article  PubMed  CAS  Google Scholar 

  • Soderpalm B (1987) Pharmacology of the benzodiazepines; with special emphasis on alprazolam. Acta Psychiatr Scand Suppl 335:39–46

    Article  PubMed  CAS  Google Scholar 

  • Squires RF, Lajtha A, Saederup E, Palkovits M (1993) Reduced [3H]flunitrazepam binding in cingulate cortex and hippocampus of postmortem schizophrenic brains: is selective loss of glutamatergic neurons associated with major psychoses? Neurochem Res 18:219–223

    Article  PubMed  CAS  Google Scholar 

  • Stadler C, Sterzer P, Schmeck K, Krebs A, Kleinschmidt A, Poustka F (2007) Reduced anterior cingulate activation in aggressive children and adolescents during affective stimulation: association with temperament traits. J Psychiatr Res 41:410–417

    Article  PubMed  Google Scholar 

  • Svensson A, Akesson P, Engel J, Soderpalm B (2003) Testosterone treatment induces behavioral disinhibition in adult male rats. Pharmacol Biochem Behav 75:481–490

    Article  PubMed  CAS  Google Scholar 

  • Sulcova A, Krsiak M (1989) Differences among 9 1,4 benzodiazepines—an ethopharmacological evaluation in mice. Psychopharmacol 97(2):157–159

    Article  CAS  Google Scholar 

  • Thiebot M, Le Bihan C, Soubrie P, Simon P (1985) Benzodiazepines reduce the tolerance to reward delay in rats. Psychopharmacology (Berl) 86:147–152

    Article  CAS  Google Scholar 

  • Treit D (1995) Evidence that tolerance develops to the anxiolytic effect of diazepam in rats. Pharmacol Biochem Behav 22:383–387

    Article  Google Scholar 

  • Weerts E, Miller L, Hood K, Miczek K (1992) Increased GABAA-dependent chloride uptake in mice selectively bred for low aggressive behavior. Psychopharmacol 108:196–204

    Article  CAS  Google Scholar 

  • Weinbroum A, Szold O, Ogorek D, Flaishon R (2001) The midazolam-induced paradox phenomenon is reversible by flumazenil. Epidemiology, patient characteristics and review of the literature. Eur J Anaesthesiol 18:789–797

    Article  PubMed  CAS  Google Scholar 

  • Weisman A, Berman M, Taylor S (1998) Effects of clorazepate, diazepam, and oxazepam on a laboratory measurement of aggression in men. Int Clin Psychopharmacol 13:183–189

    Article  PubMed  CAS  Google Scholar 

  • Woods J, Katz J, Winger G (1987) Abuse liability of benzodiazepines. Pharmacol Rev 39:251–413

    PubMed  CAS  Google Scholar 

  • Yoshimura H, Ogawa N (1991) Ethopharmacology of maternal aggression in mice: effects of diazepam and SM-3997. Eur J Pharmacol 200(1):147–153

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

The technical assistance of Ms. Karin Vieira is gratefully acknowledged. Financial support is from The National Drug Policy Coordinator (Sweden), The Swedish Medical Research Council (no. 11583), The Swedish state via the LUA Agreement, UNISINOS (Brazil), and NIAAA research grant (R01 AA 013983).

Author information

Authors and Affiliations

  1. Laboratório de Neurociências, Centro 2, UNISINOS, Av. Unisinos, 950, 93022-000, São Leopoldo, RS, Brazil

    Rosa Maria M. de Almeida, Quelin Benini & Juliana S. Betat

  2. Psicobiologia, EPM, São Paulo, Brazil

    Débora C. Hipólide

  3. Psychology Department, Tufts University, Medford, MA, USA

    Klaus A. Miczek

  4. Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, Sahlgrenska Academy, Göteborg University, Gothenburg, Sweden

    Anders I. Svensson

Authors
  1. Rosa Maria M. de Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Quelin Benini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juliana S. Betat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Débora C. Hipólide
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Klaus A. Miczek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anders I. Svensson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rosa Maria M. de Almeida.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Almeida, R.M.M., Benini, Q., Betat, J.S. et al. Heightened aggression after chronic flunitrazepam in male rats: potential links to cortical and caudate–putamen-binding sites. Psychopharmacology 197, 309–318 (2008). https://doi.org/10.1007/s00213-007-1031-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-1031-5

Keywords

Search

Navigation