Abstract
Rationale
Preclinical experimental models of pathological aggressive behavior are a sorely understudied and difficult research area.
Objectives
How valid, reliable, productive, and informative are the most frequently used animal models of excessive aggressive behavior?
Methods
The rationale, key methodological features, supporting data, and arguments as well as their disadvantages and limitations of the most frequently used animal models for excessive aggressive behavior are summarized and their validity and reliability are evaluated.
Results
Excessive aggressive behavior is validly and reliably seen in (1) a proportion of feral-derived rats and selectively bred mice; (2) rats with compromised adrenal function resulting in a hypoglucocorticoid state; (3) a significant minority of mice, rats, and monkeys after consumption of a moderate dose of alcohol; and (4) resident animals of various species after social instigation. Limitations of these procedures include restrictive animal research regulations, the requirement of expertise in surgical, pharmacological, and behavioral techniques, and the behaviorally impoverished mouse strains that are used in molecular genetics research. Promising recent initiatives for novel experimental models include aggressive behaviors that are evoked by optogenetic stimulation and induced by the manipulation of early social experiences such as isolation rearing or social stress.
Conclusions
One of the most significant challenges for animal models of excessive, potentially abnormal aggressive behavior is the characterization of distinctive neurobiological mechanisms that differ from those governing species-typical aggressive behavior. Identifying novel targets for effective intervention requires increased understanding of the distinctive molecular, cellular, and circuit mechanisms for each type of abnormal aggressive behavior.
Similar content being viewed by others
References
Azmitia EC, Liao B (1994) Dexamethasone reverses adrenalectomy-induced neuronal de-differentiation in midbrain raphe–hippocampus axis. Ann N Y Acad Sci 746:180–193
Barnett SA (1963) The rat. A study in behaviour. Aldine, Chicago
Barnett SA, Evans CS, Stoddart RC (1968) Influence of females on conflict among wild rats. J Zool 154:391–396
Belyaev DK (1979) The Wilhelmine E. Key 1978 invitational lecture. Destabilizing selection as a factor in domestication. J Hered 70:301–308
Belyaev DK, Borodin PM (1982) The influence of stress on variation and its role in evolution. Biol Zentbl 100:705–714
Berkowitz L (1993) Aggression. Its causes, consequences and control. Mc Graw Hill, New York
Blanchard RJ, Blanchard DC, Takahashi T, Kelley MJ (1977) Attack and defensive behaviour in the albino rat. Anim Behav 25:622–634
Boice R (1973) Domestication. Psychol Bull 80:215–230
Bountra C, Oppermann U, Heightman TD (2011) Animal models of epigenetic regulation in neuropsychiatric disorders. Curr Top Behav Neurosci 7:281–322
Brain PF (1986) Alcohol and aggression. Croom Helm, London
Cairns RB, MacCombie DJ, Hood KE (1983) A developmental-genetic analysis of aggressive behavior in mice: I. Behavioral outcomes. J Comp Psychol 97:69–89
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
Centenaro LA, Vieira K, Zimmermann N, Miczek KA, Lucion AB, de Almeida RM (2008) Social instigation and aggressive behavior in mice: role of 5-HT1A and 5-HT1B receptors in the prefrontal cortex. Psychopharmacology 201:237–248
Comai S, Tau M, Gobbi G (2012a) The psychopharmacology of aggressive behavior: a translational approach. Part 1: neurobiology. J Clin Psychopharmacol 32:83–94
Comai S, Tau M, Pavlovic Z, Gobbi G (2012b) The psychopharmacology of aggressive behavior: a translational approach. Part 2: clinical studies employing atypical antipsychotics, anticonvulsants, and lithium. J Clin Psychopharmacol 32:237–260
Crawley JN, Belknap JK, Collins A, Crabbe JC, Frankel W, Henderson N, Hitzemann RJ, Maxson SC, Miner LL, Silva AJ, Wehner JM, Wynshaw-Boris A, Paylor R (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology 132:107–124
da Veiga CP, Miczek KA, Lucion AB, de Almeida RMM (2011) Social instigation and aggression in postpartum female rats: role of 5-HT1A and 5-HT1B receptors in the dorsal raphé nucleus and prefrontal cortex. Psychopharmacology 213:475–487
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
de Almeida RMM, Ferrari PF, Parmigiani S, Miczek KA (2005) Escalated aggressive behavior: dopamine, serotonin and GABA. Eur J Pharmacol 526:51–64
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
de Boer SF, Caramaschi D, Natarajan D, Koolhaas JM (2009) The vicious cycle towards violence: focus on the negative feedback mechanisms of brain serotonin neurotransmission. Front Behav Neurosci 3:52
De Kloet ER, Oitzl MS, Joels M (1993) Functional implications of brain corticosteroid receptor diversity. Cell Mol Neurobiol 13:433–455
Delville Y, De Vries GJ, Ferris CF (2000) Neural connections of the anterior hypothalamus and agonistic behavior in golden hamsters. Brain Behav Evol 55:53–76
Dolan M, Anderson IM, Deakin JF (2001) Relationship between 5-HT function and impulsivity and aggression in male offenders with personality disorders. Br J Psychiatry 178:352–359
Duncan GE, Inada K, Farrington JS, Koller BH, Moy SS (2009) Neural activation deficits in a mouse genetic model of NMDA receptor hypofunction in tests of social aggression and swim stress. Brain Res 1265:186–195
Elliott FA (1977) Propranolol for the control of belligerent behavior following acute brain damage. Ann Neurol 1:489–491
Ferris CF, Melloni RH, Koppel G, Perry KW, Fuller RW, Delville Y (1997) Vasopressin/serotonin interactions in the anterior hypothalamus control aggressive behavior in golden hamsters. J Neurosci 17:4331–4340
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
Geyer MA, Markou A (2002) The role of preclinical models in the development of psychotropic drugs. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds) Neuropsychopharmacology. The fifth generation of progress. Lippincott William & Wilkins, Philadelphia, pp 445–455
Gobrogge KL, Liu Y, Young LJ, Wang Z (2009) Anterior hypothalamic vasopressin regulates pair-bonding and drug-induced aggression in a monogamous rodent. Proc Natl Acad Sci U S A 106:19144–19149
Gunnar MR, Vazquez DM (2001) Low cortisol and a flattening of expected daytime rhythm: potential indices of risk in human development. Dev Psychopathol 13:515–538
Halasz J, Liposits Z, Kruk MR, Haller J (2002) Neural background of glucocorticoid dysfunction-induced abnormal aggression in rats: involvement of fear- and stress-related structures. Eur J Neurosci 15:561–569
Haller J, Kruk MR (2006) Normal and abnormal aggression: human disorders and novel laboratory models. Neurosci Biobehav Rev 30:292–303
Haller J, van de Schraaf J, Kruk MR (2001) Deviant forms of aggression in glucocorticoid hyporeactive rats: a model for ‘pathological’ aggression? J Neuroendocrinol 13:102–107
Haller J, Halasz J, Mikics E, Kruk MR (2004) Chronic glucocorticoid deficiency-induced abnormal aggression, autonomic hypoarousal, and social deficit in rats. J Neuroendocrinol 16:550–557
Haller J, Toth 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
Haller J, Horvath Z, Bakos N (2007) The effect of buspirone on normal and hypoarousal-driven abnormal aggression in rats. Prog Neuropsychopharmacol Biol Psychiatry 31:27–31
Hasen NS, Gammie SC (2006) Maternal aggression: new insights from Egr-1. Brain Res 1108:147–156
Haspel T (1995) Beta-blockers and the treatment of aggression. Harv Rev Psychiatry 2:274–281
Heiligenberg W (1974) Processes governing behavioral states of readiness. Adv Study Behav 5:173–200
Holloway RL (1974) Primate aggression, territoriality and xenophobia: a comparative perspective. Academic, New York, p 515
Hudziak JJ, van Beijsterveldt CE, Bartels M, Rietveld MJ, Rettew DC, Derks EM, Boomsma DI (2003) Individual differences in aggression: genetic analyses by age, gender, and informant in 3-, 7-, and 10-year-old Dutch twins. Behav Genet 33:575–589
Kerman IA, Clinton SM, Bedrosian TA, Abraham AD, Rosenthal DT, Akil H, Watson SJ (2011) High novelty-seeking predicts aggression and gene expression differences within defined serotonergic cell groups. Brain Res 1419:34–45
King HD (1939) Life processes in gray Norway rats during fourteen years in captivity. Amer Anat Mem 17:1–72
Koolhaas JM, Schuurman T, Wiepkema PR (1980) The organization of intraspecific agonistic behaviour in the rat. Prog Neurobiol 15:247–268
Kornetsky C (1989) Animal models: promises and problems. In: Koob GF (ed) Animal models of depression. Birkhauser, Boston, pp 18–29
Kravitz EA, Huber R (2003) Aggression in invertebrates. Curr Opin Neurobiol 13:736–743
Lagerspetz K (1964) Studies on the aggressive behaviour of mice. Ann Acad Sci Fenn 131:1–131
Lagerspetz KMJ (1969) Aggression and aggressiveness in laboratory mice. In: Garattini S (ed) Aggressive behaviour. Excerpta Medica Foundation, Amsterdam, pp 77–85
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
Lin D, Boyle MP, Dollar P, Lee H, Lein ES, Perona P, Anderson DJ (2011) Functional identification of an aggression locus in the mouse hypothalamus. Nature 470:221–226
Lorenz K (1966) On aggression. Methuen, London
Marler P (1976) On animal aggression: the roles of strangeness and familiarity. Am Psychol 31:239–246
McBurnett K, Lahey BB, Rathouz PJ, Loeber R (2000) Low salivary cortisol and persistent aggression in boys referred for disruptive behavior. Arch Gen Psychiatry 57:38–43
McKinney WT (1989) Basis of development of animal models in psychiatry: an overview. In: Koob GF (ed) Animal models of depression. Birkhauser, Boston, pp 3–17
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
Miczek KA (1979) A new test for aggression in rats without aversive stimulation: differential effects of D-amphetamine and cocaine. Psychopharmacology 60:253–259
Miczek KA, de Boer SF (2005) Aggressive, defensive, and submissive behavior. In: Whishaw IQ, Kolb B (eds) The behavior of the laboratory rat: a handbook with tests. Oxford University Press, New York, pp 344–352
Miczek KA, DeBold JF, Van Erp AMM, Tornatzky W (1997) Alcohol, GABAA-benzodiazepine receptor complex, and aggression. In: Galanter M (ed) Recent developments in alcoholism: alcoholism and violence. Plenum, New York, pp 139–171
Miczek KA, Maxson SC, Fish EW, Faccidomo S (2001) Aggressive behavioral phenotypes in mice. Behav Brain Res 125:167–181
Miczek KA, Faccidomo S, de Almeida RMM, Bannai M, Fish EW, DeBold JF (2004a) Escalated aggressive behavior: new pharmacotherapeutic approaches and opportunities. Ann N Y Acad Sci 1036:336–355
Miczek KA, Fish EW, de Almeida RMM, Faccidomo S, DeBold JF (2004b) Role of alcohol consumption in escalation to violence. Ann N Y Acad Sci 1036:278–289
Miczek KA, de Almeida RMM, Kravitz EA, Rissman EF, de Boer SF, Raine A (2007a) Neurobiology of escalated aggression and violence. J Neurosci 27:11803–11806
Miczek KA, Faccidomo SP, Fish EW, DeBold JF (2007b) Neurochemistry and molecular neurobiology of aggressive behavior. In: Blaustein J (ed) Behavioral neurochemistry, neuroendocrinology and molecular neurobiology. Springer, New York, pp 285–336
Natarajan D, Caramaschi D (2010) Animal violence demystified. Front Behav Neurosci 4:9
Natarajan D, de Vries H, Saaltink DJ, de Boer SF, Koolhaas JM (2009a) Delineation of violence from functional aggression in mice: an ethological approach. Behav Genet 39:73–90
Natarajan D, de Vries H, de Boer SF, Koolhaas JM (2009b) Violent phenotype in SAL mice is inflexible and fixed in adulthood. Aggress Behav 35:430–436
Naumenko EV, Popova NK, Nikulina EM, Dygalo NN, Shishkina GT, Borodin PM, Markel AL (1989) Behavior, adrenocortical activity, and brain monoamines in norway rats selected for reduced aggressiveness towards man. Pharmacol Biochem Behav 33:85–91
Nelson RJ, Trainor BC (2007) Neural mechanisms of aggression. Nat Neurosci Rev 8:536–546
Neumann ID, Veenema AH, Beiderbeck DI (2010) Aggression and anxiety: social context and neurobiological links. Front Behav Neurosci 4:12
Newman EL, Chu A, Bahamon B, Takahashi A, DeBold JF, Miczek KA (2012) NMDA receptor antagonism: escalation of aggressive behavior in alcohol-drinking mice. Psychopharmacology 224:167–77
Nyberg J, Sandnabba K, Schalkwyk L, Sluyter F (2004) Genetic and environmental (inter)actions in male mouse lines selected for aggressive and nonaggressive behavior. Genes Brain Behav 3:101–109
Plyusnina IZ, Solov’eva MY, Oskina IN (2011) Effect of domestication on aggression in gray Norway rats. Behav Genet 41:583–592
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, Tenbrink L (1984) Behavior of attack-primed and attack-satiated female golden hamsters (Mesocricetus auratus). J Comp Psychol 98:66–75
Raine A, Mednick SA (1989) Biosocial longitudinal research into antisocial behavior. Rev Epidemiol Sante Publique 37:515–524
Ratey JJ, Sorgi P, O’Driscoll GA, Sands S, Daehler ML, Fletcher JR, Kadish W, Spruiell G, Polakoff S, Lindem KJ (1992) Nadolol to treat aggression and psychiatric symptomatology in chronic psychiatric inpatients: a double-blind, placebo-controlled study. J Clin Psychiatry 53:41–46
Rhee SH, Waldman ID (2002) Genetic and environmental influences on antisocial behavior: a meta-analysis of twin and adoption studies. Psychol Bull 128:490–529
Ribeiro AC, Musatov S, Shteyler A, Simanduyev S, Arrieta-Cruz I, Ogawa S, Pfaff DW (2012) siRNA silencing of estrogen receptor-alpha expression specifically in medial preoptic area neurons abolishes maternal care in female mice. Proc Nat Acad Sci U S A 109:16324–16329
Ricci LA, Knyshevski I, Melloni J (2005) Serotonin type 3 receptors stimulate offensive aggression in Syrian hamsters. Behav Brain Res 156:19–29
Roizen J (1997) Epidemiological issues in alcohol-related violence. In: Galanter M (ed) Recent developments in alcoholism. Plenum, New York, pp 7–41
Siegel A, Roeling TAP, Gregg TR, Kruk MR (1999) Neuropharmacology of brain-stimulation-evoked aggression. Neurosci Biobehav Rev 23:359–389
Simmons RK, Howard JL, Simpson DN, Akil H, Clinton SM (2012) DNA methylation in the developing hippocampus and amygdala of anxiety-prone versus risk-taking rats. Dev Neurosci 34:58–67
Sluyter F, Arseneault L, Moffitt TE, Veenema AH, de Boer SF, Koolhaas JM (2003) Toward an animal model for antisocial behavior: parallels between mice and humans. Behav Genet 33:563–574
Summers CH, Korzan WJ, Lukkes JL, Watt MJ, Forster GL, Overli O, Hoglund E, Larson ET, Ronan PJ, Matter JM, Summers TR, Renner KJ, Greenberg N (2005) Does serotonin influence aggression? Comparing regional activity before and during social interaction. Physiol Biochem Zool 78:679–694
Tellegen A, Horn JM (1972) Primary aggressive motivation in three inbred strains of mice. J Comp Physiol Psychol 78:297–304
Thayer ZM, Kuzawa CW (2011) Biological memories of past environments: epigenetic pathways to health disparities. Epigenetics 6:798–803
Tinbergen N (1968) On war and peace in animals and man: an ethologist’s approach to the biology of aggression. Science 160:1411–1418
Toth M, Halasz J, Mikics E, Barsy B, Haller J (2008) Early social deprivation induces disturbed social communication and violent aggression in adulthood. Behav Neurosci 122:849–854
Toth M, Mikics E, Tulogdi A, Aliczki M, Haller J (2011) Post-weaning social isolation induces abnormal forms of aggression in conjunction with increased glucocorticoid and autonomic stress responses. Horm Behav 60:28–36
Toth M, Tulogdi A, Biro L, Soros P, Mikics E, Haller J (2012) The neural background of hyper-emotional aggression induced by post-weaning social isolation. Behav Brain Res 233:120–129
Trainor BC, Greiwe KM, Nelson RJ (2006) Individual differences in estrogen receptor alpha in select brain nuclei are associated with individual differences in aggression. Horm Behav 50:338–345
Tulogdi A, Toth M, Halasz J, Mikics E, Fuzesi T, Haller J (2010) Brain mechanisms involved in predatory aggression are activated in a laboratory model of violent intra-specific aggression. Eur J Neurosci 32:1744–1753
Tung J, Barreiro LB, Johnson ZP, Hansen KD, Michopoulos V, Toufexis D, Michelini K, Wilson ME, Gilad Y (2012) Social environment is associated with gene regulatory variation in the rhesus macaque immune system. Proc Natl Acad Sci U S A 109:6490–6495
Van Erp A, Miczek KA (2000) Aggressive behavior, increased accumbal dopamine, and decreased cortical serotonin in rats. J Neurosci 20:9320–9325
van Oortmerssen GA, Bakker TCM (1981) Artificial selection for short and long attack latencies in wild Mus musculus domesticus. Behav Genet 11:115–126
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
Veiga CP, Aranda BCC, Stein D, Franci CR, Miczek KA, Lucion AB, de Almeida RMM (2011) Effect of social instigation and aggressive behavior on hormone levels of lactating dams and adult male Wistar rats. Psychol Neurosci 4:103–113
Virkkunen M (1985) Urinary free cortisol secretion in habitually violent offenders. Acta Psychiatr Scand 72:40–44
Volavka J (2002) Neurobiology of violence, 2nd edn. American Psychiatric, Arlington
Yudofsky SC, Silver JM, Hales RE (1990) Pharmacologic management of aggression in the elderly. J Clin Psychiatry 51(Suppl):22–28
Author information
Authors and Affiliations
Corresponding author
Additional information
This research was supported by NIH grants DA031734 and AA013983 to KAM.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Video 1
Non-vulnerable area attack. The recording shows a short episode of an aggressive encounter between a sham-operated resident and a naive intruder. The attack episode was recorded in low light; the opponents were illuminated by the infrared light source of the camcorder. The biting attack starts by lateral or sideways threat, after which the resident bends over the intruder in an attempt to bite. Accidentally, however, the mouth of the resident comes close to the belly of the opponent, i.e., a vulnerable target (see the fourth second of the recording). The deliberate avoidance of vulnerable targets by control rats is depicted by the behavior of the resident, which quickly corrects the position of its mouth, and bites the left flank of the intruder. The intruder immediately submits. This reaction to the bite is indicative of a “hard bite”. Note that the resident avoids biting the belly of the submissive opponent, despite the fact that this body area is clearly exposed and easy to bite. At the end of the bite, the intruder recovers relatively quickly, and resumes the exploration of the environment. (MPG 4845 kb)
Video 2
Vulnerable area attacks. The recording shows a short episode of an aggressive encounter between an ADXr resident and a naive intruder. The attack episode was recorded in low light; the opponents were illuminated by the infrared light source of the camcorder. At the start of the episode, both rats are in an upright posture, and reciprocally sniff each other. The resident suddenly delivers a soft bite targeting the nose of the intruder (i.e., a vulnerable area). Note that the intruder responds by upright freezing to the next approach by the resident, despite the fact that the bite was clearly soft. After a short episode of offense by the resident, the opponent falls back into submission, and is immediately bitten just above the right paw, at the border between the throat and abdomen (i.e., a vulnerable target). After this bite, the opponent remains in supine posture even after the resident stops keeping it down. Albeit not reported in earlier studies, vulnerable area attacks usually intimidate the intruder as shown by this recording. (MPG 4886 kb)
Video 3
The first segment of the video captures a resident–intruder confrontation in which the resident male displays species-typical aggressive behavior. Within seconds, the resident male initiates the attack with a bite to the posterior left flank of the intruder. Following the first attack bite, the intruder escapes and the resident pursues, attempting to nip at his hind flanks. The intruder turns to exhibit an upright defensive posture, but the resident bites several times, pauses briefly to reposition and aims the next bite at the posterior flanks of the intruder. After a short interval, the resident exhibits a sideways threat, which is rapidly followed by the delivery of two more attack bites. The resident walks away from the intruder, marking the end of the aggressive bout. Microanalysis of the resident’s species-typical aggressive behavior revealed a distinct bout of aggression and precise delivery of attack bites to the posterior flanks of the intruder. The second segment of the video captures a confrontation in which the resident male mouse displays alcohol-heightened aggression after rapidly self-administering 1 g/kg of 6 % ethanol solution (w/v). Following a brief latency, the resident delivers an initial bite to the intruder’s right forearm. As the intruder turns to escape, the resident pursues and bites the posterior flank of the intruder twice. The intruder reacts by displaying a prolonged defensive upright posture, and the resident circles the intruder to bite his flank again. Assuming a defensive position on his back, the intruder exposes his abdomen, which the resident bites repeatedly. To avoid attacks to his vulnerable underside, the intruder attempts to escape, which provokes the resident to pursue and bite the intruder’s hind flanks. After cornering the intruder, the resident pins the intruder and continues to bite the intruder’s abdomen and flanks. The intruder persists in his defensive display, and eventually resumes escape behavior. As before, the resident pursues while biting the hind flanks of the intruder. Finally, the resident walks away from the intruder to groom briefly, marking the end of the aggressive bout. From this analysis, it is evident that there are qualitative differences between species-typical and alcohol-heightened aggression. Alcohol-heightened aggression is characterized by prolonged, intense aggressive bouts and targeting attack bites at vulnerable regions. (WMV 8857 kb)
Rights and permissions
About this article
Cite this article
Miczek, K.A., de Boer, S.F. & Haller, J. Excessive aggression as model of violence: a critical evaluation of current preclinical methods. Psychopharmacology 226, 445–458 (2013). https://doi.org/10.1007/s00213-013-3008-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-013-3008-x