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Anti-aggressive effects of agonists at 5-HT1B receptors in the dorsal raphe nucleus of mice

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Abstract

Rationale

In rodents, serotonin 1B (5-HT1B) agonists specifically reduce aggressive behaviors, including several forms of escalated aggression. One form of escalated aggression is seen in mice that seek the opportunity to attack another mouse by accelerating their responding during a fixed interval (FI) schedule. Responses preceding the opportunity to attack may reflect aggressive motivation.

Objective

This study investigated the effects of two 5-HT1B receptor agonists on the motivation to fight and the performance of heightened aggression.

Materials and methods

Male mice were housed as “residents” and performed nose-poke responses on an FI 10-min schedule with the opportunity to briefly attack an “intruder” serving as the reinforcer. In the first experiment, the 5-HT1B receptor agonist, CP-94,253 (0–10 mg/kg, IP), was given 30 min before the FI 10 schedule. To confirm that CP-94,253 achieved its effects via 5-HT1B receptors, the 5HT1B/1D receptor antagonist, GR 127935 (10 mg/kg, IP) was administrated before the agonist injection. In the second experiment, the 5-HT1B agonist CP-93,129 (0–1.0 μg) was microinjected into the dorsal raphe 10 min before the FI 10 schedule.

Results

The agonists had similar effects on all behaviors. CP-94,253 and CP-93,129 significantly reduced the escalated aggression towards the intruder at doses lower than those required to affect operant responding. The highest doses of CP-94,253 (10 mg/kg) and CP-93,129 (1.0 μg) decreased the rate and accelerating pattern of responding during the FI 10 schedule; lower doses were less effective. GR 127935 antagonized CP-94,253’s effects on all other behaviors, except response rate.

Conclusions

These data extend the anti-aggressive effects of 5-HT1B agonists to a type of escalated aggression that is rewarding and further suggest that these effects are associated with actions at 5-HT1B receptors in the dorsal raphe.

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References

  • Adell A, Celada P, Artigas F (2001) The role of 5-HT1B receptors in the regulation of serotonin cell firing and release in the rat brain. J Neurochem 79:172–182

    Article  PubMed  CAS  Google Scholar 

  • Azrin NH, Hutchinson RR, McLaughlin R (1965) The opportunity for aggression as an operant reinforcer during aversive stimulation. J Exp Anal Behav 8:171–180

    Article  PubMed  CAS  Google Scholar 

  • Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152

    Article  PubMed  CAS  Google Scholar 

  • Barratt ES (1993) The use of anticonvulsants in aggression and violence. Psychopharmacol Bull 29:75–81

    PubMed  CAS  Google Scholar 

  • Bell R, Donaldson C, Gracey D (1995) Differential effects of CGS 12066B and CP-94,253 on murine social and agonistic behaviour. Pharmacol Biochem Behav 52:7–16

    Article  PubMed  CAS  Google Scholar 

  • Bouwknecht JA, Hijzen TH, van der Gugten J, Maes RA, Hen R, Olivier B (2001) Absence of 5-HT(1B) receptors is associated with impaired impulse control in male 5-HT(1B) knockout mice. Biol Psychiatry 49:557–568

    Article  PubMed  CAS  Google Scholar 

  • Buckley PF (1999) The role of typical and atypical antipsychotic medications in the management of agitation and aggression. J Clin Psychiatry 60(Suppl 10):52–60

    PubMed  Google Scholar 

  • Celada P, Puig MV, Casanovas JM, Guillzo G, Artigas F (2001) Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A GABAA and glutamate receptors. J Neurosci 21:9917–9929

    PubMed  CAS  Google Scholar 

  • Chauloff F, Courvoisier H, Moisan MP, Mormede P (1999) GR 127935 reduces basal locomotor activity and prevents RU 24969-, but not d-amphetamine-induced hyperlocomotion in the Wistar–Kyoto hyperactive (WKHA) rat. Psychopharmacology 141:326–331

    Article  Google Scholar 

  • Cherek DR, Thompson T, Heistad GT (1973) Responding maintained by the opportunity to attack during an interval food reinforcement schedule. J Exp Anal Behav 19:113–123

    Article  PubMed  CAS  Google Scholar 

  • Clark MS, Neumaier JF (2001) The 5-HT1B receptor: behavioral implications. Psychopharmacol Bull 35:170–185

    PubMed  CAS  Google Scholar 

  • Connor JL (1974) Waning and recovery of conspecific aggression in the house mouse (Mus musculus L). J Comp Physiol Psychol 87:215–227

    Article  PubMed  CAS  Google Scholar 

  • Corvaja N, Doucet G, Bolam JP (1993) Ultrastructure and synaptic targets of the raphé–nigral projection in the rat. Neuroscience 55:417–427

    Article  PubMed  CAS  Google Scholar 

  • Crowley TJ, Stynes AJ, Hydinger M, Kaufman IC (1974) Ethanol, methamphetamine, pentobarbital, morphine, and monkey social behavior. Arch Gen Psychiatry 31:829–838

    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 the medial septal area it can increase maternal aggressive behavior in rats. Psychopharmacology (Berl) 134:392–400

    Article  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 (Berl) 157:131–141

    Article  Google Scholar 

  • de Almeida RM, 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 RM, 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 receptor 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, Mocaer E, Koolhaas JM (1999) Selective antiaggressive effects of alnespirone in resident-intruder test are mediated via (5-hydroxytryptamine)1A 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, Mocaer E, Koolhaas JM (2000) Somatodendritic 5-HT(1A) autoreceptors mediate the anti-aggressive actions of 5-HT(1A) receptor agonists in rats: an ethopharmacological study with S-15535, alnespirone, and WAY-100635. Neuropsychopharmacology 23:20–33

    Article  PubMed  Google Scholar 

  • de Boer SF, van der Vegt BJ, Koolhaas JM (2003) Individual variation in aggression of feral rodent strains: a standard for the genetics of aggression and violence? Behav Genet 33:485–501

    Article  PubMed  Google Scholar 

  • De Groote L, Olivier B, Westenberg HG (2003) Role of 5-HT1B receptors in the regulation of extracellular serotonin and dopamine in the dorsal striatum of mice. Eur J Pharmacol 476:71–77

    Article  PubMed  CAS  Google Scholar 

  • 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 (Berl) 146:391–399

    Article  CAS  Google Scholar 

  • Fish EW, Sekinda M, Ferrari PF, Dirks A, Miczek KA (2000) Distress vocalizations in maternally separated mouse pups: modulation via 5-HT1A, 5-HT1B and GABAA receptors. Psychopharmacology 149:277–285

    Article  PubMed  CAS  Google Scholar 

  • Fish EW, DeBold JF, Miczek KA (2002) Aggressive behavior as a reinforcer in mice: activation by allopregnanolone. Psychopharmacology (Berl) 163:459–466

    Article  CAS  Google Scholar 

  • Fish EW, DeBold JF, Miczek KA (2005) Escalated aggression as a reward: corticosterone and GABAA positive modulators in mice. Psychopharmacology 182:116–127

    Article  PubMed  CAS  Google Scholar 

  • Fry W, Kelleher RT, Cook L (1960) A mathematical index of performance on fixed-interval schedules of reinforcement. J Exp Anal Behav 3:193–199

    Article  PubMed  CAS  Google Scholar 

  • Fuller RW (1996) The influence of fluoxetine on aggressive behavior. Neuropsychopharmacology 14:77–81

    Article  PubMed  CAS  Google Scholar 

  • Geyer MA (1996) Serotonergic functions in arousal and motor activity. Behav Brain Res 73:31–35

    Article  PubMed  CAS  Google Scholar 

  • Haller J, Kruk MR (2006) Normal and abnormal aggression: human disorders and novel laboratory models. Neurosci Biobehav Rev 30:292–303

    Article  PubMed  Google Scholar 

  • Heiligenstein JH, Beasley CM Jr, Potvin JH (1993) Fluoxetine not associated with increased aggression in controlled clinical trials. Int Clin Psychopharmacol 8:277–280

    Article  PubMed  CAS  Google Scholar 

  • Knobelman DA, Kung HF, Lucki I (2000) Regulation of extracellular concentrations of 5-hydroxytryptamine (5-HT) in mouse striatum by 5-HT(1A) and 5-HT(1B) receptors. J Pharmacol Exp Ther 292:1111–1117

    PubMed  CAS  Google Scholar 

  • Koe BK, Lebel LA, Fox CB, Macor JE (1992a) Binding and uptake studies with [H3]CP-93,129, a radiolabeled selective 5-HT1B receptor ligand. Drug Dev Res 25:67–74

    Article  CAS  Google Scholar 

  • Koe BK, Nielsen JA, Macor JE, Heym J (1992b) Biochemical and behavioral studies of the 5-HT1B receptor agonist, CP-94, 253. Drug Dev Res 26:241–250

    Article  CAS  Google Scholar 

  • Macor JE, Burkhart CA, Heym JH, Ives JL, Lebel LA, Newman ME, Nielsen JA, Ryan K, Schulz DW, Torgersen LK, Koe BK (1990) 3-(1,2,5,6-Tetrahydropyrid-4-yl) pyrrolo [3,2-b] pyrid-5-one: a potent and selective serotonin (5HT1B) agonist and rotationally restricted phenolic analogue of 5-methoxy-3-(1,2,5,6-tetrahydropyrid-4-yl) indole. J Med Chem 33:2087–2093

    Article  PubMed  CAS  Google Scholar 

  • Martinez M, Guillen-Salazar F, Salvador A, Simon VM (1995) Successful intermale aggression and conditioned place preference in mice. Physiol Behav 58:323–328

    Article  PubMed  CAS  Google Scholar 

  • Meisel RL, Joppa MA (1994) Conditioned place preference in female hamsters following aggressive or sexual encounters. Physiol Behav 56:1115–1118

    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 (Berl) 157:421–429

    Article  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 (Berl) 57:47–55

    Article  CAS  Google Scholar 

  • Miczek KA, Maxson SC, Fish EW, Faccidomo S (2001) Aggressive behavioral phenotypes in mice. Behav Brain Res 125:167–181

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Miczek KA, Faccidomo SP, Fish EW, DeBold JF (2006) Neurochemistry and molecular neurobiology of aggressive behavior. In: JD Blaustein (ed) Behavioral neurochemistry, neuroendocrinology and molecular neurobiology. Handbook of neurochemistry and molecular biology. Kluwer, New York

    Google Scholar 

  • Monroe RR (1975) Anticonvulsants in the treatment of aggression. J Nerv Ment Dis 160:119–126

    Article  PubMed  CAS  Google Scholar 

  • Mos J, Olivier B, Poth M, Aken H (1992) The effects of intraventricular administration of eltoprazine, 1-(3-trifluoromethylphenyl) piperazine hydrochloride and 8-OH-DPAT 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 raphe administration of eltoprazine TF and Ipp and 8-OH-DPAT on resident intruder aggression in the rat. Eur J Pharmacol 238:411–415

    Article  PubMed  CAS  Google Scholar 

  • Mos J, Vanaken HHM, van Oorschot R, Olivier B (1996) Chronic treatment with eltoprazine does not lead to tolerance in its antiaggressive action, in contrast to haloperidol. Eur Neuropsychopharmacol 6:1–7

    Article  PubMed  CAS  Google Scholar 

  • Olivier B, Mos J (1986) Serenics and aggression. Stress Med 2:197–209

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Olivier B, Mos J, Rasmussen D (1990) Behavioural pharmacology of the serenic, eltoprazine. Rev Drug Metab Drug Interact 8:31–83

    CAS  Google Scholar 

  • Olivier B, Mos J, Van Oorschot R, Hen R (1995) Serotonin receptors and animal models of aggressive behavior. Pharmacopsychiatry 28:80–90

    Article  PubMed  Google Scholar 

  • Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates. Second edition. San Diego: Academic Press

  • Puig MV, Artigas F, Celada P (2005) Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: involvement of serotonin and GABA. Cereb Cortex 15:1–14

    Article  PubMed  Google Scholar 

  • Ramboz S, Saudou F, Amara DA, Belzung C, Segu L, Misslin R, Buhot MC, Hen R (1996) 5-HT1B receptor knock out: behavioral consequences. Behav Brain Res 73:305–312

    Article  PubMed  CAS  Google Scholar 

  • Ratey JJ, Gordon A (1993) The psychopharmacology of aggression: toward a new day. Psychopharmacol Bull 29:65–73

    PubMed  CAS  Google Scholar 

  • Sari Y (2004) Serotonin1B receptors: from protein to physiological function and behavior. Neurosci Biobehav Rev 28:565–582

    Article  PubMed  CAS  Google Scholar 

  • Sari Y, Miquel MC, Brisorgueil MJ, Ruiz G, Doucet E, Hamon M et al (1999) Cellular and subcellular localization of 5-hydroxytryptamine1b receptors in the rat central nervous system: immunocytochemical, autoradiographic and lesion studies. Neuroscience 88:899–915

    Article  PubMed  CAS  Google Scholar 

  • Saudou F, Amara DA, Dierich A, Lemeur M, Ramboz S, Segu L et al (1994) Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science 265:1875–1878

    Article  PubMed  CAS  Google Scholar 

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

    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 autoradiographic study with eltoprazine. Pharmacol Biochem Behav 38:447–458

    Article  PubMed  CAS  Google Scholar 

  • Silverman AP (1965) Ethological and statistical analysis of drug effects on the social behaviour of laboratory rats. Br J Pharmacol 24:579–590

    CAS  Google Scholar 

  • Tellegen A, Horn JM, Legrand RG (1969) Opportunity for aggression as a reinforcer in mice. Psychon Sci 14:104–105

    Google Scholar 

  • van der Vegt BJ, Lieuwes N, van de Wall EHEM, Kato K, Moya-Albiol L, Martinez-Sanchis S, de Boer SF, Koolhaas JM (2003a) Activation of serotonergic neurotransmission during the performance of aggressive behavior in rats. Behav Neurosci 117:667–674

    Article  PubMed  Google Scholar 

  • van der Vegt BJ, Lieuwes N, Cremers TIFH, de Boer SF, Koolhaas JM (2003b) Cerebrospinal fluid monoamine and metabolite concentrations and aggression in rats. Horm Behav 44:199–208

    Article  PubMed  CAS  Google Scholar 

  • Vitiello B, Stoff DM (1997) Subtypes of aggression and their relevance to child psychiatry. J Am Acad Child Adolesc Psych 36:307–315

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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Acknowledgments

This research was supported by a grant from the NIAAA (KAM) and by the Research Institute for Health Fundamentals, Ajinomoto Co., Inc.

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Authors and Affiliations

  1. Department of Psychology, Tufts University, Medford and Boston, MA, USA

    Makoto Bannai, Eric W. Fish, Sara Faccidomo & Klaus A. Miczek

  2. Department of Psychiatry, Pharmacology, and Neuroscience, Tufts University, 530 Boston Ave. (Bacon Hall), Medford, MA, 02155, USA

    Klaus A. Miczek

  3. Research Institute for Health Fundamentals, Ajinomoto Co., Inc., Kawasaki, Japan

    Makoto Bannai

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  1. Makoto Bannai
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Correspondence to Klaus A. Miczek.

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Bannai, M., Fish, E.W., Faccidomo, S. et al. Anti-aggressive effects of agonists at 5-HT1B receptors in the dorsal raphe nucleus of mice. Psychopharmacology 193, 295–304 (2007). https://doi.org/10.1007/s00213-007-0780-5

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  • DOI: https://doi.org/10.1007/s00213-007-0780-5

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