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Social instigation and aggressive behavior in mice: role of 5-HT1A and 5-HT1B receptors in the prefrontal cortex

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Abstract

Rationale

Social instigation is used in rodents to induce high levels of aggression, a pattern of behavior with certain parallels to that of violent individuals. This procedure consists of a brief exposure to a provocative stimulus male, before direct confrontation with an intruder. Studies using 5-HT1A and 5-HT1B receptor agonists show an effective reduction in aggressive behavior. An important site of action for these drugs is the ventral orbitofrontal cortex (VO PFC), an area of the brain which is particularly relevant in the inhibitory control of aggressive and impulsive behavior.

Objectives

The objectives of the study are to assess the anti-aggressive effects of 5-HT1A and 5-HT1B agonist receptors [8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) and CP-93,129] in the VO PFC of socially provoked male mice. To confirm the specificity of the receptor, 5-HT1A and 5-HT1B antagonist receptors (WAY-100,635 and SB-224,289) were microinjected into the same area, in order to reverse the agonist effects.

Results

8-OH-DPAT (0.56 and 1.0 μg) reduced the frequency of attack bites. The lowest dose of CP-93,129 (0.1 μg) also decreased the number of attack bites and lateral threats. 5-HT1A and 5-HT1B receptor agonists differed in their effects on non-aggressive activities, the former decreasing rearing and grooming, and the latter, increasing these acts. Specific participation of the 1A and 1B receptors was verified by reversal of anti-aggressive effects using selective antagonists WAY-100,635 (10.0 μg) and SB-224,289 (1.0 μg).

Conclusions

The decrease in aggressiveness observed with microinjections of 5-HT1A and 5-HT1B receptor agonists into the VO PFC of socially provoked mice, supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner.

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References

  • Ahlenius S, Larsson K, Wijkström A (1991) Behavioral and biochemical effects of the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT in the rat. Eur J Pharmacol 200:259–266

    Article  PubMed  CAS  Google Scholar 

  • Anderson SW, Bechara A, Damasio H, Tranel D, Damasio AR (1999) Impairment of social and moral behavior related to early damage in human prefrontal cortex. Nat Neurosci 2:1032–1037

    Article  PubMed  CAS  Google Scholar 

  • Bannai M, Fish EW, Faccidomo S, Miczek KA (2007) Anti-aggressive effects of agonists at 5-HT1B receptors in the dorsal raphe nucleus of mice. Psychopharmacology 193(2):295–304

    Article  PubMed  CAS  Google Scholar 

  • Bell R, Hobson H (1994) 5-HT1A receptor influences on rodent social and agonistic behavior: a review and empirical study. Neurosci Biobehav Rev 18:325–338

    Article  PubMed  CAS  Google Scholar 

  • Best M, Willians M, Coccaro EF (2002) Evidence for a dysfunctional prefrontal circuit in patients with an impulsive aggressive disorder. Psychol 99:8448–8453

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Boschert U, Amara DA, Segu L, Hen R (1994) The mouse 5-hydroxytryptamine1B receptor is localized predominantly on axon terminals. Neuroscience 58:167–182

    Article  PubMed  CAS  Google Scholar 

  • Brazell MP, Marsden CA, Nisbet AP, Routledge C (1985) The 5-HT1 receptor agonist RU-24969 decreases 5-hydroxytryptamine (5-HT) release and metabolism in the rat frontal cortex in vitro and in vivo. Br J Pharmacol 86:209–216

    PubMed  CAS  Google Scholar 

  • Caldwell EE, Miczek KA (2008) Long-term citalopram maintenance in mice: selective reduction of alcohol-heightened aggression. Psychopharmacology 196:407–416

    Article  PubMed  CAS  Google Scholar 

  • Caramaschi D, De Boer SF, Koolhaas JM (2007) Differential role of the 5-HT1A receptor in aggressive and non-aggressive mice: An across-strain comparison. Physiol Behav 90:590–601

    Article  PubMed  CAS  Google Scholar 

  • Cleare AJ, Bond AJ (1995) The effect of tryptophan depletion and enhancement on subjective and behavioral aggression in normal male subjects. Psychopharmacology 118:72–81

    Article  PubMed  CAS  Google Scholar 

  • Coccaro EF, Siever LJ, Klar HM, Maurer G, Cochrane K, Cooper TB, Mohs RC, Davis KL (1989) Serotonergic studies in patients with affective and personality disorders. Correlates with suicidal and impulsive aggressive behavior. Arch Gen Psychiatry 46(7):587–599

    PubMed  CAS  Google Scholar 

  • Crabbe JC, Phillips TJ, Feller DJ, Hen R, Wenger CD, Lessov CN, Schafer GL (1996) Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors. Nat Genet 14:98–101

    Article  PubMed  CAS  Google Scholar 

  • Davidson RJ, Putnam KM, Larson CL (2000) Dysfunction in the neural circuitry of emotion regulation - a possible prelude to violence. Science 289(5479):591–594

    Article  PubMed  CAS  Google Scholar 

  • De Almeida RMM, Lucion AB (1997) 8-OH-DPAT in the median raphe, dorsal periaqueductal gray and corticomedial amygdala nucleus decreases, but in the medial septal area it can increase maternal aggressive behavior in rats. Psychopharmacology 134:392–400

    Article  PubMed  Google Scholar 

  • De Almeida RMM, Miczek KA (2002) Aggression escalated by social instigation or by discontinuation of reinforcement (“frustration”) in mice: inhibition by anpirtoline—a 5-HT1B receptor agonist. Neuropsychopharmacology 27:171–181

    Article  PubMed  Google Scholar 

  • De Almeida RMM, Nikulina EM, Faccidomo S, Fish EW, Miczek KA (2001) Zolmitriptan—a 5-HT1B/D agonist, alcohol, and aggression in mice. Psychopharmacology 157:131–141

    Article  PubMed  Google Scholar 

  • De Almeida RMM, Ferrari PF, Parmigiani S, Miczek KA (2005) Escalated aggressive behavior: Dopamine, serotonin and GABA. Eur J Pharmacol 526:51–64

    Article  PubMed  CAS  Google Scholar 

  • De Almeida RMM, Rosa MM, Santos DM, Saft DM, Benini Q, Miczek KA (2006) 5-HT1B receptors, ventral orbitofrontal cortex, and aggressive behavior in mice. Psychopharmacology 185:441–450

    Article  PubMed  CAS  Google Scholar 

  • De Boer SF, Koolhaas JM (2005) 5-HT1A and 5-HT1B receptors agonists and aggression: A pharmacological challenge of the serotonin deficiency hypothesis. Eur J Pharmacol 526:125–139

    Article  PubMed  CAS  Google Scholar 

  • De Boer SF, Lesourd M, Mocaër E, Koolhaas JM (1999) Selective antiaggressive effects of alnespirone in resident–intruder test are mediated via 5-hydroxytryptaminelA receptors: a comparative pharmacological study with 8-hydroxy-2-dipropylaminotetralin, ipsapirone, buspirone, eltoprazine, and WAY-100635. J Pharmacol Exp Ther 288:1125–1133

    PubMed  Google Scholar 

  • De Boer SF, Lesourd M, Mocaër E, Koolhaas JM (2000) Somatodendritic 5-HT(1A) autoreceptors mediate the anti-aggressive actions of 5-HT(1A) receptors agonist in rats: an ethopharmacological study with S-15535, alnespirone, and WAY-100635. Neuropsychopharmacology 23:20–33

    Article  PubMed  Google Scholar 

  • Dugar A, Lakoski JM (1997) Serotonergic function of aging hippocampal CA3 pyramidal neurons: electrophysiological assessment following administration of 5,7-dyhydroxytriptamine in the fimbria-fornix and cingulum bundle. J Neurosci Res 47:58–67

    Article  PubMed  CAS  Google Scholar 

  • Faccidomo S, Bannai M, Miczek KA (2008) Escalated aggression after alcohol drinking in male mice: dorsal raphé and prefrontal cortex serotonin and 5-HT(1B) receptors. Neuropsychopharmacol Feb 27 doi:10.1038/npp.2008.7

  • Fish EW, Faccidomo S, Miczek KA (1999) Aggression heightened by alcohol or social instigation in mice: reduction by the 5-HT1B receptor agonist CP-94,253. Psychopharmacology 146:391–399

    Article  PubMed  CAS  Google Scholar 

  • Fish EW, McKenzie-Quirk SD, Bannai M, Miczek KA (2008) 5-HT(1B) receptor inhibition of alcohol-heightened aggression in mice: comparison to drinking and running. Psychopharmacology 197:145–156

    Article  PubMed  CAS  Google Scholar 

  • Frankfurt M, Mendelson SD, McKittrick CR, McEwen BS (1993) Alterations of serotonin receptor-binding in the hypothalamus following acute denervation. Brain Res 601:349–352

    Article  PubMed  CAS  Google Scholar 

  • Frankfurt M, McKittrick CR, Mendelson SD, McEwen BS (1994) Effect of 5,7-dyhydroxytryptamine, ovariectomy and gonadal-steroids on serotonin receptor-binding in rat brain. Neuroendocrinology 59:245–250

    Article  PubMed  CAS  Google Scholar 

  • Grafman J, Schwab K, Warden D, Pridgen BS, Brown HR (1996) Frontal lobe injuries, violence and aggression: a report of the Vietnam head injury study. Neurology 46:1231–1238

    PubMed  CAS  Google Scholar 

  • Halász J, Tóth M, Kalló I, Liposits Z, Haller J (2006) The activation of prefrontal cortical neurons in aggression—a double labeling study. Behav Brain Res 175:166–175

    Article  PubMed  Google Scholar 

  • Haller J, Tóth M, Halasz J, De Boer SF (2006) Patterns of violent aggression-induced brain c-fos expression in male mice selected for aggressiveness. Physiol Behav 88:173–182

    Article  PubMed  CAS  Google Scholar 

  • Hertel P, Nomikos GG, Svensson TH (1999) The antipsychotic drug risperidone interacts with auto- and hetero-receptors regulating serotonin output in the rat frontal cortex. Neuropharmacology 38:1175–1184

    Article  PubMed  CAS  Google Scholar 

  • Joppa MA, Rowe RK, Meisel RL (1997) Effects of serotonin 1A and 1B receptor agonists on social aggression in male and female syrian hamsters. Pharmacol Biochem Behav 58:349–353

    Article  PubMed  CAS  Google Scholar 

  • Larsson K, Ahlenius S (1999) Brain and sexual behavior. Ann N Y Acad Sci 877:292–308

    Google Scholar 

  • Linnoila M, Virkkunen M, Scheinin M, Nuutila A, Rimon R, Goodwin FK (1983) Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from nonimpulsive violent behavior. Life Sci 33:2609–2614

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Mendoza D, Guilar-Bravo H, Swanson HH (1998) Combined effects of Gepirone and (+) WAY 100135 on territorial aggression in mice. Pharmacol Biochem Behav 61:1–8

    Article  PubMed  CAS  Google Scholar 

  • Manrique C, Francoisbellan AM, Segu L, Becquet D, Hery M, Faudon M, Hery F (1994) Impairment of serotoninergic transmission is followed by adaptive-changes in 5-HT1B binding-sites in the rat suprachiasmatic nucleus. Brain Res 663:93–100

    Article  PubMed  CAS  Google Scholar 

  • Mehlman PT, Higley JD, Faucher I, Lilly AA, Taub DM, Vickers J, Suomi SJ, Linnoila M (1994) Low CSF 5-HIAA concentrations and severe aggression and impaired impulsive control in non-human primates. Am J Psychiatry 151:1485–1491

    PubMed  CAS  Google Scholar 

  • Miczek KA, O’Donnell JM (1978) Intruder-evoked aggression in isolated and nonisolated mice: effects of psychomotor stimulants and L-dopa. Psychopharmacology 57:47–55

    Article  PubMed  CAS  Google Scholar 

  • Miczek KA, De Almeida RMM (2001) Oral drug self-administration in the home cage of mice: alcohol-heightened aggression and inhibition by the 5-HT1B agonist anpirtoline. Psychopharmacology 157:421–429

    Article  PubMed  CAS  Google Scholar 

  • Miczek KA, Barros HM, Sakoda L, Weerts EM (1998a) Alcohol and heightened aggression in individual mice. Alcohol Clin Exp Res 22:1698–1705

    PubMed  CAS  Google Scholar 

  • Miczek KA, Hussain S, Faccidomo S (1998b) Alcohol-heightened aggression in mice: attenuation by 5-HT1A receptor agonists. Psychopharmacology 139(1–2):160–168

    Article  PubMed  CAS  Google Scholar 

  • Miczek KA, Fish EW, De Bold JF, De Almeida RMM (2002) Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and gamma-aminobutyric acid systems. Psychopharmacology 163:434–458

    Article  PubMed  CAS  Google Scholar 

  • Miczek KA, Faccidomo S, De Almeida RMM, Bannai M, Fish EW, Debold JF (2004) Escalated aggressive behavior: new pharmacotherapeutic approaches and opportunities. Ann NY Acad Sci 1036:336–355

    Article  PubMed  CAS  Google Scholar 

  • Mos J, Olivier B, Poth M, Van Aken H (1992) The effects of intraventricular administration of eltoprazine, I-(3-trifluoromethylphenyl) piperazine hydrochloride and 8-hydroxy-2-(di-n-propylamino) tetralin on resident intruder aggression in the rat. Eur J Pharmacol 212:295–298

    Article  PubMed  CAS  Google Scholar 

  • Mos J, Olivier B, Poth M, Van Oorschot R, Van Aken H (1993) The effects of dorsal raphé administration of eltoprazine, TFMPP and 8-OH-DPAT on resident aggression in the rat. Eur J Pharmacol 238:411–415

    Article  PubMed  CAS  Google Scholar 

  • Olivier B (2004) Serotonin and aggression. Ann NY Acad Sci 1036:382–392

    Article  PubMed  CAS  Google Scholar 

  • Olivier B, Oorschot RV (2005) 5-HT1B receptors and aggression: A review. Eur J Pharmacol 526:207–217

    Article  PubMed  CAS  Google Scholar 

  • Olivier B, Mos J, Tulp M, Schipper J, Bevan P (1989) Modulatory action of serotonin in aggressive behavior. In: Archer T, Bevan P, Cools AR (eds) Behavioural pharmacology of 5-HT. Lawrence Erlbaum Associates, New Jersey, pp 89–115

    Google Scholar 

  • Olivier B, Mos J, De Koning P, Mak M (1994) Serenics. Prog Drug Res 42:167–302

    PubMed  CAS  Google Scholar 

  • Parsons LH, Weiss F, Koob GF (1998) Serotonin1B receptor stimulation enhances cocaine reinforcement. J Neurosci 18:10078–10089

    PubMed  CAS  Google Scholar 

  • Paxinos G, Franklin KBJ (1997) The mouse brain in stereotaxic coordinates. Academic Press, New York

    Google Scholar 

  • Potegal M (1991) Attack priming and satiation in female golden hamsters: tests of some alternatives to the aggression arousal interpretation. Agress Behav 17:327–335

    Article  Google Scholar 

  • Raine A, Buchsbaum MS, Stanley J, Lottenberg S, Abel L, Stoddard J (1994) Selective reductions in prefrontal glucose metabolism in murderers. Biol Psychiatry 38:342–343

    Google Scholar 

  • Raine A, Lencz T, Bihrle S, Lacasse L, Colletti P (2000) Reduced prefrontal gray matter volume and reduced autonomic activity in antisocial personality disorder. Arch Gen Psychiatry 57:119–127

    Article  PubMed  CAS  Google Scholar 

  • Riad M, Garcia S, Watkins KC, Jodoin N, Doucet E, Langlois X, el Mestikawy S, Hamon M, Descarries L (2000) Somatodendritic localization of 5-HT1A and preterminal axonal localization of 5-HT1B serotonin receptors in adult rat brain. J Comp Neurol 417:181–94

    Article  PubMed  CAS  Google Scholar 

  • Roberts C, Price GW, Middlemiss DN (2001) Ligands for the investigation of 5-HT autoreceptor function. Brain Res Bull 56:463–469

    Article  PubMed  CAS  Google Scholar 

  • Sarhan H, Fillion G (1999) Differential sensitivity of 5-HT1B auto and heteroreceptors. Naunyn-Schmiedeberg’s Arch Pharmacol 360:382–390 doi:10.1007/s002109900067IN

    Article  CAS  Google Scholar 

  • Sanchez C, Arnt J, Hyttel J, Moltzen EK (1993) The role of serotonergic mechanisms in inhibition of isolation-induced aggression in male mice. Psychopharmacology 110:53–59

    Article  PubMed  CAS  Google Scholar 

  • Sijbesma H, Schipper J, de Kloet ER, Mos J, van Aken H, Olivier B (1991) Postsynaptic 5-HT1 receptors and offensive aggression in rats: a combined behavioural and authoradiographic study with eltoprazine. Pharmacol Biochem Behav 38(2):447–458

    Google Scholar 

  • Simansky KJ, Vaidya AH (1990) Behavioral mechanisms for the anorectic action of the serotonin (5-HT) uptake inhibitor sertraline in rats: comparison with directly acting 5-HT agonists. Brain Res Bull. 25:953–60

    Article  PubMed  CAS  Google Scholar 

  • Tuinier S, Verhoeven WM, Van Praag HM (1995) Cerebrospinal fluid 5-hydroxyindoleacetic acid and aggression: a critical reappraisal of the clinical data. Int Clin Psychopharmacol 10:147–156

    Article  PubMed  CAS  Google Scholar 

  • Tompkins EC, Clemento AJ, Taylor DP, Perhach Jr JL (1980) Inhibition of aggressive behavior in rhesus monkeys by buspirone. Res Commun Psychol Psychiatr Behav 5:337–352

    CAS  Google Scholar 

  • Valzelli L, Garattini S (1968) Behavioral changes and 5-hydroxytryptamine turnover in animals. Adv Pharmacol 6B:249–260

    Article  Google Scholar 

  • Van de Kar LD, Li Q, Cabrera TM, Brownfield MS, Battaglia G (1998) Alterations in 8-hydroxy-2-(dipropylamino)tetralin-induced neuroendocrine responses after 5,7-dyhydroxytryptamine-induced denervation of serotonergic neurons. J Pharmacol Exp Ther 286:256–262

    PubMed  Google Scholar 

  • Van Der Vegt BJ, De Boer SF, Buwalda B, De Ruiter AJ, De Jong JG, Koolhaas JM (2001) Enhanced sensitivity of postynaptic serotonin-1A receptors in rats and mice with high trait aggression. Physiol Behav 74:205–211

    Article  PubMed  Google Scholar 

  • Veiga CP, Miczek KA, Lucion AB, De Almeida RMM (2007) Effect of 5-HT1B receptor agonists injected into the prefrontal cortex on maternal aggression in rats. Braz J Med Biol Res 40:825–830

    Article  PubMed  CAS  Google Scholar 

  • Volavka J (1995) Neurobiology of violence. American Psychiatric, Washington

    Google Scholar 

  • Winslow JT, Miczek KA (1984) Habituation of aggressive behavior in mice: a parametric study. Agress Behav 10:103–113

    Article  Google Scholar 

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Acknowledgements

The authors would like to thank Mr. Marcelo Grilo for his technical support and Mr. Dirson Stein for his important assistance and animal care. CNPq and FAPERGS supported this research.

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Authors and Affiliations

  1. Departamento de Fisiologia, Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Lígia Aline Centenaro & Aldo Bolten Lucion

  2. Laboratório de Neurociências e Programa de Pós-Graduação em Psicologia, Ciências da Saúde, Universidade do Vale do Rio dos Sinos, São Leopoldo, RS, Brazil

    Karin Vieira, Nicolle Zimmermann & Rosa Maria Martins de Almeida

  3. Departments of Psychology, Pharmacology, Neuroscience and Psychiatry, Tufts University, Medford and Boston, MA, USA

    Klaus A. Miczek

  4. Laboratório de Neurociências, Universidade do Vale do Rio dos Sinos, Centro 2, Av. Unisinos 950, CEP: 93.022-000, Cristo Rei, São Leopoldo, São Leopoldo, RS, Brazil

    Rosa Maria Martins de Almeida

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  1. Lígia Aline Centenaro
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  2. Karin Vieira
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  3. Nicolle Zimmermann
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  4. Klaus A. Miczek
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  6. Rosa Maria Martins de Almeida
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Correspondence to Rosa Maria Martins de Almeida.

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Centenaro, L.A., Vieira, K., Zimmermann, N. et al. Social instigation and aggressive behavior in mice: role of 5-HT1A and 5-HT1B receptors in the prefrontal cortex. Psychopharmacology 201, 237–248 (2008). https://doi.org/10.1007/s00213-008-1269-6

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