Abstract
Experiments with social instigation or the omission of scheduled reinforcement show that serotonergic mechanisms may be involved in escalated aggression in animals. 5-HT1B receptor agonists have anti-aggressive effects in individuals who show moderate as well as high levels of aggression. The present study compared the effects of the 5-HT1B agonist anpirtoline (0.125–1.5 mg/kg) on (1) species-typical aggressive behavior in male mice, (2) aggression “instigated” or primed by prior exposure to the opponent, and (3) aggression heightened by “frustration” caused by omission of scheduled reinforcement. The effects of anpirtoline on species-typical behavior were also assessed after pretreatment with the 5-HT1B/1D receptor antagonist GR127935 (10 mg/kg). Anpirtoline, like other 5-HT1B agonists (CP-94,253, zolmitriptan), decreased both instigated and frustration-heightened aggression, while motor behavior was unaffected. The aggression-inhibiting effects of anpirtoline were blocked by pretreatment with GR127935. The current results indicate that the 5-HT1B receptor is critically involved in the modulation of escalated aggression.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Amsel A, Roussel J . (1952): Motivational properties of frustration. 1. Effect on a running response of the addition of frustration to the motivational complex. J Exp Psychol 43: 363–368
Azrin NH, Hutchinson RR, Hake DF . (1966): Extinction-induced aggression. J Exp Anal Behav 9: 191–204
Boschert U, Amara DA, Segu L, Hen R . (1994): The mouse 5-hydroxytryptamine 1B receptor is localized perdominatly on axon terminals. Neuroscience 58: 167–182
Bouwknecht JA, Hijzen TH, van der GJ, Maes RA, Hen R, Olivier B . (2001): Absence of 5-HT1B receptors is associated with impaired impulse control in male 5-HT1B knockout mice. Biol Psychiatry 49: 557–568
Brain PF . (1975): What does individual housing mean to a mouse? Life Sci 16: 187–200
Caprara GV . (1982): A comparison of the frustration aggression and emotional susceptibility hypotheses. Aggressive Behav 8: 234–236
Cherek DR, Pickens R . (1970): Schedule-induced aggression as a function of fixed-ratio value. J Exp Anal Behav 14: 309–311
Coccaro EF . (1989): Central serotonin and impulsive aggression. Br J Psychiatry 155: 52–62
Davidson C, Stamford JA . (1995): Evidence that 5-hydroxytryptamine release in rat dorsal raphe nucleus is controlled by 5-HT1A, 5HT1B and 5-HT1D autoreceptors. Br J Pharmacol 114: 1107–1109
de Almeida RMM, Lucion AB . (1994): Effects of intacerebroventricular administration of 5-HT receptor agonists on the maternal aggression of rats. Eur J Pharmacol 264: 445–448
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 (Berl) 134: 392–400
de Almeida RMM, Nikulina E, Faccidomo S, Fish E, Miczek KA . (2001): Zolmitriptan, a 5-HT1B/D receptor agonist, alcohol, and aggression in male mice. Psychopharmacology 157 2: 131–141
Dollard J, Doob L, Miller N, Mowrer O, Sears R . (1939): Frustration and Aggression. New Haven, Yale University Press
Evenden JL, Ryan CN . (1996): The pharmacology of impulsive behaviour in rats: the effects of drugs on response choice with varying delays of reinforcement. Psychopharmacology (Berl) 128: 161–170
Falk JL . (1971): The nature and determinants of adjunctive behavior. Physiol Behav 6: 577–588
Falk JL . (1977): The origin and functions of adjunctive behavior. Anim Learn Behav 5: 325–335
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
Garattini S, Giacalone E, Valzelli L . (1967): Isolation, aggressiveness and brain 5-hydroxytryptamine turnover. J Pharm Pharmacol 19: 338–339
Gothert M . (1992): 5-hydroxytryptamine receptors: an example for the complexity of chemical transmission of information in the brain. Arzneimittel-Forschung/Drug Res 42: 238–246
Heiligenberg W . (1974): Processing governing behavioral states of readiness. In Lehmrman DS, Rosenblatt JS, Hinde RA, Shaw F (eds), Advances in the Study of Behavior, 5 New York, Academic Press.
Higley JD, Bennett AJ . (1999): Central nervous system serotonin and personality as variables contributing to excessive alcohol consumption in non-human primates. Alcohol Alcohol 34: 402–418
Hillegaart V, Ahlenius S . (1998): Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181. Br J Pharmacol 125: 1733–1743
Huang YY, Grailhe R, Arango V, Hen R, Mann JJ . (1999): Relationship of psychopathology to the human serotonin 1B genotype and receptor binding kinectics in postmortem brain tissue. Neuropsychopharmacology 21: 238–246
Kelly DD . (1974): The experimental imperative: laboratory analyses of aggressive behaviors. In: Frazier SH (ed), Aggression. Research Publications Association for Research in Nervous and Mental Diseases. Baltimore, Williams and Wilkins Co
Krsiak M . (1975): Timid singly-housed mice: their value in prediction of psychotropic activity of drugs. Br J Pharmacol 55: 141–150
Krsiak M . (1979): Effects of drugs on behaviour of aggressive mice. Br J Pharmacol 65: 525–533
Lagerspetz K, Hautojarvi S . (1967): The effect of prior aggressive or sexual arousal on subsequent aggressive or sexual reactions in male mice. Scand J Psychol 8: 1–6
Lagerspetz KMJ . (1969): Aggression and aggressiveness in laboratory mice. In: Garattini S (ed), Aggressive Behaviour. Amsterdam, Excerpta Medica Foundation
Lappalainen J, Long JC, Eggert M, Ozaki N, Robin RW, Brown GL, Naukkarinen H, Virkkunen M, Linnoila M, Goldman D . (1998): Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch Gen Psychiatry 55: 989–994
Lee MD, Aloyo VJ, Fluharty SJ, Simansky KJ . (1998): Infusion of the serotonin1B (5-HT1B) agonist CP-93,129 into the parabrachial nucleus potently and selectively reduces food intake in rats. Psychopharmacology (Berl) 136: 304–307
Lesch KP, Merschdorf U . (2000): Impulsivity, aggression, and serotonin: a molecular psychobiological perspective. Behav Sci Law 18: 581–604
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
Looney TA, Cohen PS . (1982): Aggression induced by intermittent positive reinforcement. Neurosci Biobehav Rev 6: 15–37
Maurel S, Schreiber R, De Vry J . (1998): Role of 5-HT1B, 5-HT2A and 5-HT2C receptors in the generalization of 5-HT receptor agonists to the ethanol cue in the rat. Behav Pharmacol 9: 337–343
Metzenauer P, Barnes NM, Costall B, Gozlan H, Hamon M, Kelly ME, Murphy DA, Naylor RJ . (1992): Anxiolytic-like actions of anpirtoline in a mouse light-dark aversion paradigm. Biobehav Rev 3: 527–529
Miczek KA . (1982): Ethological analysis of drug action on aggression, defense and defeat. In: Spiegelstein MY (eds), Behavioral Models and the Analysis of Drug Action. Amsterdam, Elsevier
Miczek KA . (2001): Research on Animal Aggression: Emerging Successes for Understanding Determinants of Human Violence. In: Carrol ME, Overmier JB (eds), Animal Research and Human Health: Advancing Human Welfare through Behavioral Science. Washington, DC: American Psychological Association
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 (4): 421–429
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
Miczek KA, Hussain S, Faccidomo S . (1998): Alcohol-heightened aggression in mice: attenuation by 5-HT1A receptor agonists. Psychopharmacology (Berl) 139: 160–168
Miczek KA, Maxson SC, Fish EW, Faccidomo S . (2001): Aggressive behavioral phenotypes in mice. Behav Brain Res 125: 167–181
Miczek KA, O'Donnell JM . (1980): Alcohol and chlordiazepoxide increase suppressed aggression in mice. Psychopharmacology (Berl) 69: 39–44
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
Mos J, Olivier B, Poth M, Van Oorschot R, Van Aken H . (1993): The effects of dorsal raphe administration of eltoprazine, TFMPP and 8-OH- DPAT on resident intruder aggression in the rat. Eur J Pharmacol 238: 411–415
National Research Council. (1996): Guide for the care and use of laboratory animals. Washington, DC: National Academy Press
O'Neill MF, Conway MW . (2001): Role of 5-HT1A and 5-HT1B receptors in the mediation of behavior in the forced swim test in mice. Neuropsychopharmacology 24: 391–398
O'Neill MF, Fernandez AG, Palacios JM . (1996): GR 127935 blocks the locomotor and antidepressant-like effects of RU 24969 and the action of antidepressants in the mouse tail suspension test. Pharmacol Biochem Behav 53: 535–539
Olivier B, Mos J, Van Oorschot R, Hen R . (1995): Serotonin receptors and animal models of aggressive behavior. Pharmacopsychiatry 28: 80–90
Parsons LH, Weiss F, Koob GF . (1998): Serotonin 1B receptor stimulation enhances cocaine reinforcement. J Neurosci 18: 10078–10089
Pauwels PJ, Tardiff S, Palmier C, Wurch T, Colpaert FC . (1997): How efficacious are 5-HT1B/D receptor ligands: an answer from GTPγS binding studies with stably transfected C-glial cell lines. Neuropharmacology 36: 499–512
Payne AP, Andrews MJ, Wilson CA . (1984): Housing, fighting and biogenic amines in the midbrain and hypothalamus of the golden hamster. In: Miczek KA (ed), Ethopharmacological Aggression Research New York, Alan R. Liss
Potegal M . (1991): Attack priming and satiation in female golden hamsters: tests of some alternatives to the aggression arousal interpretation. Aggress Behav 17: 327–335
Potegal M . (1992): Time course of aggressive arousal in female hamsters and male rats. Behav Neural Biol 58: 120–124
Potegal M, Tenbrink L . (1984): Behavior of attack-primed and attack-satiated female golden hamsters (Mesocricetus auratus). J Comp Psychol 98: 66–75
Ramboz S, Saudou F, Amara DA, Belzung C, Segu L, Misslin R, Buhot MC, Hen R . (1995): 5-HT1B receptor knock out – Behavioral consequences. Behav Brain Res 73: 305–312
Rilke O, Will K, Jahkel M, Oehler J . (2001): Behavioral and neurochemical effects of anpirtoline and citalopram in isolated and group housed mice. Prog Neuropsychopharmacol Biol Psychiatry 25: 1125–1144
Sanchez C, Arnt J, Hyttel J, Moltzen EK . (1993): The role of serotonergic mechanisms in inhibition of isolation-induced aggression in male mice. Psychopharmacology (Berl) 110: 53–59
Saudou F, Amara DA, Dierich A, Lemeur M, Ramboz S, Segu L, Buhot MC, Hen R . (1994): Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Sci 265: 1875–1878
Schlicker E, Werner U, Hamon M, Gozlan H, Nickel B, Szelenyi I, Gothert M . (1992): Anpirtoline, a novel, highly potent 5-HT1B receptor agonist with antinociceptive/antidepressant-like actions in rodents. Br J Pharmacol 105: 732–738
Stenfors C, Yu H, Svante BR . (2000): Enhanced 5-HT metabolism and synthesis rate by the new selective r5-HT1B receptor antagonist, NAS-181 in the rat brain. Neuropharmacology 39: 553–560
Swedberg MD, Shannon HE, Nickel B, Goldberg SR . (1992): D-16949 (anpirtoline): a novel serotonergic (5-HT1B) psychotherapeutic agent assessed by its discriminative effects in the rat. J Pharmacol Exp Ther 263: 1015–1022
Tellegen A, Horn JM . (1972): Primary aggressive motivation in three inbred strains of mice. J Comp Physiol Psychol 78: 297–304
Thompson T, Bloom W . (1966): Aggressive behavior and extinction-induced response-rate increase. Psychonomic Sci 5: 335–336
Thor DH, Carr WJ . (1979): Sex and aggression: Competitive mating strategy in the male rat. Behav Neural Biol 26: 261–265
Thor DH, Flannelly KJ . (1979): Copulation and intermale aggression in rats. J Comp Physiol Psychol 93: 223–228
Valzelli L, Giacalone E, Garattini S . (1967): Pharmacological control of aggressive behavior in mice. Eur J Pharmacol 2: 144–146
van Erp AMM, Miczek KA . (2000): Aggressive behavior, increased accumbal dopamine and decreased cortical seroton.
Virkkunen M, De Jong J, Barko J, Goodwin FK, Linnoila M . (1989): Relationship of psychobiological variables to recidivism in violent offenders and impulsive fire setters. Arch Gen Psychiatry 46: 600–603
Acknowledgements
This research was supported by USPHS research grant AA05122 and DA02632 (KAM, PI). RMMdA was supported by a fellowship from CAPES (Brazil) and UNISINOS (Brazil). We thank Mr. J. Thomas Sopko for outstanding technical assistance,.and Mr. E. Fish for valuable advice.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
de Almeida, R., Miczek, K. Aggression Escalated by Social Instigation or by Discontinuation of Reinforcement (“Frustration”) in Mice: Inhibition by Anpirtoline: A 5-HT1B Receptor Agonist. Neuropsychopharmacol 27, 171–181 (2002). https://doi.org/10.1016/S0893-133X(02)00291-9
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(02)00291-9
Keywords
This article is cited by
-
Modelling sexual violence in male rats: the sexual aggression test (SxAT)
Translational Psychiatry (2022)
-
Recent advances in the study of aggression
Neuropsychopharmacology (2019)
-
Dopamine disruption increases negotiation for cooperative interactions in a fish
Scientific Reports (2016)
-
Stress and the social brain: behavioural effects and neurobiological mechanisms
Nature Reviews Neuroscience (2015)
-
Regulation of Potential-Dependent Ca2+ Channels by Serotonin 5-HT1B Receptors in Different Populations of Hippocampal Neurons
Neuroscience and Behavioral Physiology (2014)