Aggression and Violent Behavior 18 (2013) 195–203

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Aggression and Violent Behavior

Aggressive behavior: A comprehensive review of its neurochemical mechanisms

and management
Solomon Umukoro a,⁎, Aderemi C. Aladeokin b, Anthony T. Eduviere a
a
Department of Pharmacology and Therapeutics, University of Ibadan, Oyo, Nigeria
b
Department of Pharmacology College of Health Sciences, Osun State University, Osun, Nigeria

a r t i c l e i n f o a b s t r a c t

Article history: Aggression is a deliberate series of actions that lead to harm, injury, or destruction of another organism, and is
Received 20 October 2011 the most common factor promoting violent crimes. Beyond being the immediate cause of physical injury, ag-
Received in revised form 1 November 2012 gressive behavior also produces profound long term emotional disabilities in its victims. When outburst of
Accepted 6 November 2012
aggression is comorbid with DSM-IV-defined neuropsychiatric disorders, the offenders are usually given psy-
Available online 27 November 2012
chiatric care; however, when they appear normal or healthy, their most likely fate is punishment by the law.
Keywords:
This punitive approach often increases aggression, thereby promoting the propensity for violent crimes.
Aggression Antipsychotics are the drugs commonly used for treatment of aggression and violent outbursts. However,
Types the uses of these drugs have serious side effects of catalepsy or impairment of sensorimotor performance.
Neurochemicals They also affect the defense or flight capabilities of organisms, which further limit their usefulness in aggres-
Animal models sion. Thus, there is a critical need to search for agents that can selectively reduce aggression without affecting
Treatment other behaviors or causing any serious unwanted side effects. This review focuses on the types, neurochem-
ical bases, and animal models of aggression, with a comprehensive appraisal of the pharmacological approach
to the treatment of the disorder.
© 2012 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
2. Types of aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
2.1. Bimodal classification of aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
3. Neurochemical basis of aggressive behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
3.1. Serotonin deficiency hypothesis of aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
3.2. Factors regulating 5-HT levels and aggressive tendencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
3.3. 5-HT receptors relevant in aggressive behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
3.4. Other major neurochemicals implicated in aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
3.4.1. GABA and glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
3.4.2. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
3.4.3. Noradrenaline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
4. Animal models of offensive aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
4.1. Isolation-induced offensive aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
4.2. Resident–intruder offensive behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
4.3. Offensive behavior induced by electrical brain stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
4.4. Maternal aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
5. Animal models of defensive behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
5.1. Defensive behavior in resident–intruder paradigm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
6. Limits to animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

⁎ Corresponding author at: Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria. Tel.: +234 8130897439; fax: +234 2413546.
E-mail address: umusolo@yahoo.com (S. Umukoro).

1359-1789/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.avb.2012.11.002
196 S. Umukoro et al. / Aggression and Violent Behavior 18 (2013) 195–203
7. Pharmacological treatment of aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. Conclusion and challenges for future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Aggression is a deliberate series of actions that lead to harm, injury, or
destruction of another organism and is the most common factor promot-
ing violent crimes. Beyond being the immediate cause of physical injury,
aggressive behavior also produces profound long term emotional disabil-
ities in its victims (Weinshenker & Siegel, 2002). When outburst of ag-
gression is comorbid with DSM-IV-defined neuropsychiatric disorders,
the offenders are usually given psychiatric care, but when they appear
normal or healthy, their most likely fate is punishment by law
(Weinshenker & Siegel, 2002). However, this punitive approach often
increases aggression, thereby promoting the propensity for violent
crimes.
Although aggression is detrimental to the society, it also serves as a
useful defensive purpose for obtaining the desired goal of self-
preservation in life threatening events (Moffitt et al., 2008; Moyer,
1968; Siegel & Victoroff, 2009). Mental illness, prolonged stress, poverty,
and drug abuse are common factors that contribute to the higher rate of
violence or aggressive outbursts (Gowin, Swann, Moeller, & Lane, 2010;
Moffitt et al., 2008; Moss, Yao, & Panzak, 1990; Siegel & Victoroff, 2009;
Weinshenker & Siegel, 2002). In vulnerable individuals, stress in particu-
lar, can lead to a subtype of depression characterized by anger, anxiety,
and aggression (Barnett, Fagan, & Booker, 1991; Weinshenker & Siegel,
2002). Stress might be a strong factor that can precipitate aggression
and predicts the severity of developing violence behavior (Barnett
et al., 1991).
The major limitation in the study of aggression is the lack of suit-
able animal models with predictive validity of human aggression that
can provide insight into the neural mechanisms underlying the disor-
der, as well as new targets of therapeutic intervention (Blanchard &
Blanchard, 2003; Gowin et al., 2010; Moffitt et al., 2008; Miczek,
Fish, De Bold, & De Almeida, 2002; Miczek, Weerts, Haney, & Tidey,
1994). The use of antipsychotics in the treatment of aggression is lim-
ited by serious adverse effects, which necessitate the search for
agents that can selectively reduce aggression without affecting
other behaviors or causing any serious unwanted side effects. Current
research is now focused on the development of serenics (compounds
with selective anti-aggressive activity) that stimulate specific subsets
of 5-HT receptors that are critically involved in the initiation and ex-
ecution of aggressive acts (Miczek et al., 2002; Moffitt et al., 2008).
However, the complex neural mechanisms and lack of a unified clas-
sification scheme for the categorization of human aggression has con-
tributed greatly to the slow pace in the development of specific
anti-aggressive agents (Weinshenker & Siegel, 2002). The aim of
this review is to discuss the types, neurochemical bases, and animal
models of aggression, with an appraisal of the pharmacological ap-
proach to the treatment of the disorder.
2. Types of aggression
The lack of a unified classification scheme for the categorization of
human aggression has contributed greatly to the slow pace in the devel-
opment of new medicines with specific anti-aggressive properties
(Weinshenker & Siegel, 2002). Various types of aggression have been
described in literature based on the factors that trigger it. Moyer
(1968) classified aggression into the seven different categories:
(1) Fear induced-aggression: This occurs when the animal is placed in
a position where escape is denied and turns, instead, to attack a second
animal perceived as a threat. (2) Maternal-induced aggression: This is
200
201
201
a form of an attack that occurs when an animal is placed close to its
young ones and a second animal approaches. (3) Intermale-induced
aggression: An attack occurring by a male toward another male, but
not a female, in its immediate environment. (4) Irritable aggression: An
attack occurring in response to a threat, intimidation, or to an environ-
mental condition which is irritating. (5) Sex-related aggression: In
humans, sexual arousal is frequently associated with increased levels of
hostility or hostile fantasies. In animals, components of aggressive be-
havior are sometimes associated with sexual acts. The aggressive and
sexual aspects appear as components of the same behavioral act, thus,
creating difficulties in classifying these behaviors. (6) Territorial aggres-
sion: An attack occurring when an intruder enters into an area that an
animal has determined for itself to be its own domain. This is commonly
known as a resident–intruder model. Most often, tests involving the res-
ident–intruder model utilize animals of the same species although a res-
ident animal might also attack an intruder of a different species (Malone
et al., 1998; Weinshenker & Siegel, 2002). (7) Predatory aggression: Spe-
cifically triggered by the presence of a prey within the visual field of the
predator; this response can be elicited in experimental conditions by
stimulating the lateral hypothalamus of the cat (Siegel, Roeling, Gregg,
& Kruk, 1999). The response is characterized by stalking of an anesthe-
tized rat, which is followed by a bite to the back of its neck, which con-
tinues until stimulation is terminated (Siegel et al., 1999). It is evident
that all these forms of aggression are meant for the dual purposes of sur-
vival and reproduction whether for obtaining food, access to a mate or
protection. However, the central question that may be asked is whether
these aggressive behaviors are related by a common neural mechanism
or to different mechanisms underlying them.
2.1. Bimodal classification of aggression
A number of investigators have attempted to classify aggressive
behavior in animals or humans into affective defense and predatory
attack (Weinshenker & Siegel, 2002). Affective defense is an aggres-
sive response based on the presence of fear and/or threat, which
may be real or perceived. Predatory attack has been understudied
relative to affective defense, and consists of a purposeful and
goal-directed attack with the absence of sympathetic arousal
(Weinshenker & Siegel, 2002). Thus, the seven types of aggression be-
long to one of two categories, predatory attack or affective defense
behavior (Eichelman, 1985; Malone et al., 1998). All categories
of aggression that include fear-induced, maternal, intermale, sex-
related, irritable, and territorial appear to have a similar common fea-
ture, namely an aggressive response based on the presence of
elements of fear and/or threat that may be real or perceived. Thus,
these categories of aggression may be classified as affective defense
(Weinshenker & Siegel, 2002). The motivation frequently triggering
aggressive responses may be pain, a threat of another organism of
the same or different species, and territory perceived by the animal
in question as its own (Malone et al., 1998). Moyer showed the
unique characteristics associated with affective defense, which are
submission and appeasement, together with their associated postural
positions. Moreover, these forms of behavior have been clearly
described in different species, including mice, rats, cats, dogs, and
primates. Moyer argues that submission reflects an aggression-
inhibiting mechanism that has survival value by signaling to the dom-
inant animal that the fight is over (Weinshenker & Siegel, 2002). In
addition, the posture adopted by the defeated animal makes it diffi-
cult for the dominant animal to continue its aggressive acts. The
 S. Umukoro et al. / Aggression and Violent Behavior 18 (2013) 195–203
ultimate goal is that the fighting is terminated, thereby preventing
further injury to the defeated animal (Weinshenker & Siegel,
2002).
Predatory attack, in contrast to affective defense, is limited to a
single category of aggressive behavior. Predatory aggression is typi-
cally interspecies while others are expressed as intraspecific in inter-
actions. Predatory behavior has been studied most extensively in the
cat where this response can be elicited by electrical stimulation of the
lateral hypothalamus (Weinshenker & Siegel, 2002). An experiment
using a rodent model of predatory attack has also been described
(Sandnabba, 1995). It is believed that predatory attack should not
be regarded as a form of aggression, but rather as a behavioral strat-
egy associated with feeding behavior (Adams, 1980; Weinshenker &
Siegel, 2002). However, in humans, affective and predatory compo-
nents of aggression may appear together.
In the literature, aggression has been classified into two subtypes:
instrumental and emotional aggression. Instrumental aggression is
considered harm with a purpose (Weinshenker & Siegel, 2002). It is a
harmful behavior used specifically to obtain something desirable. Ag-
gression caused by self-defense falls into this category. It is used to
obtain the desired goal of self-preservation. Emotional aggression is
the act of “inflicting harm for its own sake” (Weinshenker & Siegel,
2002). Revenge is a type of emotional aggression, and people attempt
to enact revenge because of the pleasure they derive from the act itself.
Emotional aggression is referred to as reactive or affective aggression in
some sources (Malone et al., 1998; Weinshenker & Siegel, 2002).
However, the distinction of aggression into offensive and defensive
behaviors appears to receive a wider acceptance, with well-defined
brain mechanisms (Malone et al., 1998). Offensive behavior is charac-
terized by the initiative of the aggressor and with the intent to cause
damage to the opponent (Malone et al., 1998; Weinshenker & Siegel,
2002). In contrast, defensive behavior lacks active approach (initiative),
and the defensive animal inflicts no intentional damage.
Predatory aggression represents a separate classification of
aggression that seems to be primarily driven by appetite mechanisms
and apparently has a distinct brain system involved (Malone et al.,
1998; Malone et al., 1998; Weinshenker & Siegel, 2002). In the frame-
work of evolution, these behaviors are meant to encourage survival of
the fittest, to disperse populations, to aid adaptation to threatening
environments, and generally to improve the probability of individual
and species survival (Weinshenker & Siegel, 2002).
3. Neurochemical basis of aggressive behaviors
The neural mechanism that mediates aggression is still poorly
understood even though several neurochemicals are implicated in the
pathogenesis of this behavioral trait. Serotonin, or 5-hydroxytrypta-
mine (5-HT), is the major neurochemical implicated in aggression and
violent crimes. It has been shown to play a key role in the initiation,
execution and treatment of aggressive acts (Berman, Tracy, & Coccaro,
1997; Gowin et al., 2010). Several studies have confirmed a negative
correlation between serotonin levels in the brain and aggression
(Adams, 1979; Berman et al., 1997; Gowin et al., 2010). The negative
correlation between serotonin turnover and aggression is commonly
known as the serotonin-deficiency hypothesis of aggression (Berman
et al., 1997). According to this hypothesis, aggression is characterized
by low brain 5-HT levels (Berman et al., 1997; Brown et al., 1982; de
Boer & Koolhaas, 2005).
3.1. Serotonin deficiency hypothesis of aggression
The original serotonin deficiency hypothesis was based on a nega-
tive correlation between trait-like impulsive aggression/violence and
the CSF concentration of the 5-HT metabolite in humans and other pri-
mates (Berman et al., 1997; Brown et al., 1982). In humans, low levels of
the serotonin metabolite (5-HIAA) in the cerebrospinal fluid have been
197
associated with aggression and other forms of antisocial behavior,
including assault, arson, murder, and child abuse as well as in violent
forms of suicide. Moreover, a substantial number of non-primate animal
studies have revealed that the propensity to exhibit excessive and
abnormal forms of aggression is similarly linked to long-term reduced
brain 5-HT activity (Miczek et al., 2002). In addition, studies have
shown that chronically lowering or heightening brain 5-HT provokes
increased or reduced levels of aggressive behavior respectively, further
supporting the serotonergic deficiency hypothesis of aggressive behav-
ior (Blanchard & Blanchard, 2003; Weinshenker & Siegel, 2002).
Initially, the association was found in isolated mice that became aggres-
sive while reducing their 5-HT turnover, an indicator of 5-HT neuro-
transmission and consequent degradation (Garattini, 1967; Giacolone,
Tansella, Valzelli, & Gurattini, 1968). Similar studies in humans and
non-human primates confirm a negative correlation between serotonin
turnover and aggressive tendencies (Brown et al., 1982; Miczek et al.,
2002).
3.2. Factors regulating 5-HT levels and aggressive tendencies
The neural activity of serotonergic system depends on the integration
of several processes that involve 5-HT synthesis, release, reuptake, deg-
radation and receptor activation. Changes in any one or more of these
processes might be responsible for the reduced 5-HT metabolites seen
in aggressive and violent individuals. Thus, these sites might serve as tar-
gets for development of drugs for the control of aggression. Diets which
are low in tryptophan, a precursor of serotonin which acts to increase its
concentrations in the brain, have been shown to increase aggression in
animals and humans (Cleare & Bond, 1995). The relevance of the seroto-
nergic pathway in violent behavior is further supported by the ability of
para-chlorophenylalanine, an irreversible inhibitor of 5-HT biosynthesis
to heighten aggression in animals (de Boer & Koolhaas, 2005; Conner,
Stolk, Barchas, Dement, & Levine, 1970; Valzelli, Bernaconi, & Gurattini,
1981; Vergnes, Depaulis, & Boehrer, 1986). Further, a single nucleotide
polymorphism in the coding region of tryptophan hydroxylase, the
enzyme for 5-HT synthesis gene, resulted in anger and aggression in
healthy humans (de Boer & Koolhaas, 2005). The level of serotonergic
activity is strongly regulated by 5-HT1A/B receptors and may, therefore,
play crucial roles in the mediation of aggression and violent
behavior (Pineyro & Blier, 1999). The 5-HT1A/B receptors are located
pre-synaptically as autoreceptors on the soma and dendrites of
serotonergic neurons, as well as post-synaptically on non-serotonergic
neurons in several cortico-limbic areas that receive 5-HT terminals
(Pineyro & Blier, 1999). Activation of somatodentritic 5-HT1A/B
autoreceptors by 5-HT or 5-HT1A/B agonists has been shown to potently
decrease the rate of firing of 5-HT neurons and decrease the rate of
5-HT synthesis and release or turnover (de Boer & Koolhaas, 2005;
Pineyro & Blier, 1999). The 5-HT1A/B agonists were found to exert potent
anti-aggressive activity, which indicates the important inhibitory role for
these receptors in the motivation or execution of aggressive acts (de Boer
& Koolhaas, 2005; Pineyro & Blier, 1999).
The extracellular levels of 5-HT also depend on its reuptake and met-
abolic degradation by monoamine oxidase (MAO) enzymes. Serotonin
selective reuptake inhibitors (SSRIs), which increase the availability of
serotonin in the brain and are used commonly for the treatment of de-
pression, were also effective for the treatment of aggression (Olivier,
Mos, van der Heyden, & Hartog, 1989). The depletion of MAO-A gene
in rodents produced an increase in aggressiveness (Cases et al., 1995).
These findings indicate that availability of 5-HT at the synapses influ-
ences aggressive behavior.
3.3. 5-HT receptors relevant in aggressive behavior
The effects of serotonin in the nervous system are mediated by a
family of different 5-HT receptor subtypes, many of which contain
distinct subunits and differ in their mechanism of signal transduction.
198 S. Umukoro et al. / Aggression and Violent Behavior 18 (2013) 195–203
Although studies have shown inverse relationship between 5-HT
levels in the brain and aggressive behavior, the roles of 5-HT receptor
subtypes in aggression are yet to be clearly elucidated. Pharmacolog-
ical investigations and the use of knockout approaches in rodents
revealed that 5-HT1 and 5-HT2 receptors, and their respective sub-
types are more relevant in the expression of aggressive behavior
(de Boer & Koolhaas, 2005; Pineyro & Blier, 1999).
Animal studies have shown that the use of specific agonists
especially for 5-HT1 receptor subtypes leads to a reduction in aggressive
behavior (de Boer & Koolhaas, 2005). Conversely, inhibition of 5-HT1
receptor subtypes using specific antagonists generally promotes aggres-
sion, although this relationship is not very consistent (Pineyro & Blier,
1999; de Boer & Koolhaas, 2005). The 5-HT1A/B receptors that regulate
serotonergic system have shown to be more relevant in the mediation
of aggression and violence (de Almeida & Miczek, 2002; de Boer &
Koolhaas, 2005; Pineyro & Blier, 1999). The 5-HTA1 agonists exert
potent anti-aggressive activity (de Boer & Koolhaas, 2005; Gowin
et al., 2010), but a number of 5-HT1A antagonists also decreased aggres-
sion (Mendoza et al., 1999). Such a discrepancy may be the result of
these agents interacting with either pre- or post-synaptic 5-HT1A recep-
tors, other 5-HT receptor subtypes, or other neurotransmitter systems
(Sanchez, Arnt, Hyttel, & Moltzen, 1993).
Regarding the 5-HT1B receptor, knockout mice lacking this gene dis-
play heightened aggression compared to wild-types, indicating an
important role for this receptor subtype in the mediation of aggression
(Saudou et al., 1994). Activation of 5-HT1B receptors inhibits aggressive
behavior despite decreasing serotonergic tone; presumably the behav-
ioral effects of 5-HT1B-receptor activation reflect modulation of other
neurotransmitter systems (de Boer & Koolhaas, 2005).
The effect of 5-HT1A and 5-HT1B receptors in the control of 5-HT
tone and vice versa aggression suggests that there are other 5-HT re-
ceptors that might be playing a crucial role in violent behavior.
Studies have also shown that there is reduced functionality of post-
synaptic 5-HT2A/C heteroreceptors in aggressive individuals (de Boer &
Koolhaas, 2005). Studies examining the effect of the 5-HT2 receptor
reveal that the selective 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-
iodophenyl)-2-aminopropane decreases aggression at high doses, but
also elicits a characteristic side effect of 5-HT stimulation termed “wet
dog shaking” (Sloviter, Drust, & Conner, 1978). However, the relation-
ship is not as clear with 5-HT2 antagonists, as several studies have
shown conflicting results. While Sanchez et al. (1993) report no effects
of 5-HT2 antagonists on aggression, studies by White, Kucharik, and
Moyer (1991) and Olivier, Mos, van Oorschot, and Hen (1995) provide
evidence that the specific 5-HT2 antagonists reduce aggression. Antago-
nism of 5-HT2 receptors appears to decrease aggression in animal
models, and this effect may explain the ability of newer antipsychotic
agents (which, unlike the older medications, block 5-HT2 receptors) to
produce a reduction in aggression and agitation independent of effects
on psychotic symptoms (Buckley et al., 1995). Studies suggest that the
overall frequency of assaults, use of seclusion, mechanical restraint,
and chemical restraint in patients with schizophrenia who are treated
with clozapine are reduced over traditional neuroleptics (Ratey,
Leveroni, Kilmer, Gutheil, & Swartz, 1993).
The presence of 5-HT3 receptors in the amygdaloid complex and ce-
rebral cortex suggests that these receptors may play potential roles in
the mediation of aggression (Tecott, Maricq, & Julius, 1993). 5-HT recep-
tors are involved in fast-excitatory activities that are crucial in emotional
and behavioral responses, as well as in other, less defined functions such
as sensory perception, memory, and motor control (Tecott et al., 1993).
White et al. (1991) and Sanchez et al. (1993) examined the effects of
5-HT3 receptor antagonists, ondansetron, and zacopride in rodent
inter-male aggression. They concluded that these compounds have no
effect on aggression. The continued discovery of 5-HT-receptor subtypes
indicates that further study will be needed to clarify the specific roles of
the various receptor subtypes and their interactions in aggression.
Nelson and Trainor (2007) emphasized the need to examine aggressive
behavior in knockout mice that lack other 5-HT-receptor subtypes, as
well as in tissue-specific 5-HT-receptor knockout mice, to discriminate
between pre- and postsynaptic effects of 5-HT signaling aggression.
3.4. Other major neurochemicals implicated in aggression
The reciprocal interactions of serotonin with other several transmit-
ters and hormones provide further evidence that this indolamine medi-
ates impulsive aggressive behavior. The ultimate effect of serotonin on
aggressive behavior appears to be related to its actions on several trans-
mitter substances (Nelson & Trainor, 2007). The other major neuro-
chemicals linked to aggression include gamma-aminobutyric acid
(GABA), glutamate, dopamine, and noradrenaline (Nelson & Trainor,
2007). Neuroadaptive changes in dopamine, GABA, glutamate, and nor-
adrenaline have been found after repeated aggressive experiences, both
in the perpetrator and in the victim (Nelson & Trainor, 2007). However,
agents that affect these neurochemicals are known to cause serious side
effects, which tend to limit their usefulness in aggression (de Almeida
et al., 2005).
3.4.1. GABA and glutamate
Gamma-aminobutyric acid (GABA) is the primary mediator of
inhibitory transmission in the mammalian central nervous system.
GABA is involved in the modulation of aggression and studies have
shown low levels of this transmitter in aggressive individuals. Thus,
it may be expected that substances that potentiate GABAergic neuro-
transmission should reduce aggressive activity (de Almeida et al.,
2005; Miczek et al., 2002). Allosteric modulators of GABAA receptors,
such as benzodiazepines and barbiturates, influence aggression levels
in rodents, with an inverted U-shaped dose–response curve; low
doses evoke aggression, whereas high doses reduce aggressive behav-
ior (Gowin et al., 2010; Miczek et al., 2002). The facilitative effects of
alcohol on aggression are well known, and also occur through alloste-
ric modulation of GABAA receptors. Alcohol increases the duration
and frequency of opening of chloride ion channels and thereby
enhances GABA mediated chloride flux. GABA-receptor agonists
reduce aggression in many people, presumably by reducing arousal
(de Almeida et al., 2005; Gowin et al., 2010). Drugs which act on
these systems, such as barbiturates, benzodiazepines and morphine,
reduce arousal as well as aggression.
Glutamate is an excitatory amino acid that has been implicated in
the genesis of aggression and violent behavior. Glutamate by increasing
neuronal excitation may contribute to an increase in aggression, and is
implicated in the expression of defensive rage behavior and in exagger-
ated emotional reactivity (Haller, Makara, & Kruk, 1998). Compounds
with inhibitory effect against glutamate NMDA receptors may exhibit
a nonspecific effect on aggression, mainly due to sedation.
3.4.2. Dopamine
The mesocorticolimbic dopaminergic neurons are involved in the
mediation of aggressive behavior and also contribute to other moti-
vated behaviors, such as reproductive and maternal behaviors, as
well as food and drug intake. The D2-receptor antagonist haloperidol
has been used effectively for decades to treat aggressive patients,
especially those with psychotic disorder (de Almeida et al., 2005).
However, haloperidol has sedating and locomotor-impairing effects,
which make it and other D2-receptor antagonists unattractive for
long-term treatment of aggression (de Almeida et al., 2005). Antago-
nists of both the D1 and D2 receptors have greater propensity to cause
impairment of sensory motor performance (de Almeida et al., 2005).
Dopaminergic receptor agonists have been shown to induce defensive
behavior in cats and increase level of dopamine precedes the attack
and defensive behavior in cats and amphetamine-induced dopamine
release can increase aggression in rodents (Nelson & Trainor, 2007).
However, the role of dopamine in the control of aggression still
remains speculative (de Almeida et al., 2005).
 S. Umukoro et al. / Aggression and Violent Behavior 18 (2013) 195–203
3.4.3. Noradrenaline
Noradrenaline is involved in many functions, which are critical in
the regulation of mood and behavior. Although no consistent rela-
tionship between noradrenaline and aggression has been established,
pharmacological manipulations of noradrenaline levels or specific
noradrenergic receptors indicate that noradrenaline signaling facili-
tates aggression (Nelson & Trainor, 2007). Norepinephrine's relation-
ship with aggressive behavior may best be explained in terms of the
stress–response system and the type of aggressive behavior elicited
(Koolhaas et al., 1999). Agonistic encounters are generally perceived
as stressful and arousing that lead to elevated levels of noradrenaline,
both centrally and peripherally (Haller et al., 1998). Noradrenaline
may affect aggression on three different levels: the hormonal level,
the sympathetic autonomous nervous system, and the central ner-
vous system (CNS), in different, but functionally synergistic ways.
Part of these effects may arise in indirect ways that are by no means
specific to aggressive behavior; however, they are functionally rele-
vant to it (Nelson & Trainor, 2007). Other effects may affect brain
mechanisms specifically involved in aggression. Hormonal catechol-
amines (adrenaline and noradrenaline) are involved in metabolic
preparations of the organism for the prospective fight; the sympa-
thetic system ensures appropriate cardiovascular reaction, while the
CNS noradrenergic system prepares the animal for the prospective
fight (Haller et al., 1998; Nelson & Trainor, 2007). The major indirect
CNS effects include decrease in pain sensitivity; and the enhancement
of memory, which is very relevant for the survival of the animal.
Amphetamine usage has also been linked with increased aggres-
sion and this is probably because its major action within the brain is
to facilitate the release of pro-aggression neurotransmitters such as
noradrenaline and dopamine. The α- and β-adrenergic-receptor sub-
types have been shown to mediate aggressive effect of noradrenaline
(Haller et al., 1998).
4. Animal models of offensive aggression
The development of animal models that mimic specific aggressive dis-
orders could lead to additional insights into the mechanisms that underlie
aggression and treatment options. There are two major types of animal
models of aggression: offensive and defensive aggressive paradigms
(Adams, 1979; Malone et al., 1998; Weinshenker & Siegel, 2002). Models
of offensive aggression include isolation-induced aggression, resident–in-
truder paradigm, and maternal aggression (Adams, 1979; Malick, 1979;
Valzelli, 1973). Defensive aggression models include the characteristic of
the lack of an active approach, and usually no wounds are made on the
attacker (Adams, 1979; Bond & Lader, 1988). Examples of this model
are foot shock or pain induced aggression, and the resident–intruder par-
adigm or maternal aggression in response to an intruder (Malick, 1979;
Valzelli, 1973). Therefore, this kind of defensive behavior model reflects
a different form of aggression than the offensive aggression models.
Defensive aggression models have not been as extensively used in drug
development, perhaps because they are viewed as less “pathological”
(Malone et al., 1998; Weinshenker & Siegel, 2002).
4.1. Isolation-induced offensive aggression
Isolation-induced aggression in mice is an animal model of offen-
sive aggression with strong predictive validity toward human aggres-
sion (Malick, 1979). A manipulation often used to induce aggression
is isolation of male animals, typically mice, for several weeks. Many
such isolated animals, on encountering another male, will exhibit at-
tack behavior (Malick, 1979). The test is commonly conducted in the
home cage of the isolated male mouse. However, performing the test
in a neutral arena is more attractive because the situation delivers a
mix of offensive, defensive and flight behaviors, which are not seen
or are infrequently seen in the home cage confrontation (Olivier &
Van Dalen, 1982).
199
The effects of several drugs including benzodiazepines, neurolep-
tics, psychostimulants, alcohol, 5-HT1A-receptor agonists, serenics
(5-HT1A/1B-receptor agonists), and selective serotonin reuptake in-
hibitors have been investigated in this model (Miczek, DeBold, van
Erp, & Tornatzky, 1997). Benzodiazepines show inverse U-shaped
dose–response curves in this model. Benzodiazepines at low doses,
produced increases in aggression, whereas at high doses, decreases
are observed (Miczek et al., 1997; Olivier & Van Dalen, 1982).
Psychostimulants enhanced locomotor activity thereby interfering
with the normal agonistic behavior (Miczek et al., 1997). Amphet-
amine, a psychostimulant, produced no effect on aggression, but it
decreased the locomotor threshold, indicating its stimulatory action
without having specific effects on aggression (Miczek et al., 1997).
Antipsychotics, chlorpromazine, and haloperidol exert antiaggressive
effect, but also caused nonspecific effects such as impairment of
sensorimotor performance (Miczek et al., 1997). However, serenics
(serotonergic 5-HT1B/1A-receptor agonists) exhibited a highly selec-
tive antiaggressive activity, reducing aggression specifically without
affecting other behaviors or causing any unwanted side effects
(Olivier, Mos, Hartog, & Rasmussen, 1990).
4.2. Resident–intruder offensive behavior
The resident–intruder model is a unique animal paradigm for dif-
ferent aspects of social interactions and also provides an excellent
predictive validity toward human aggression (Miczek, 1974; Olivier
& Van Dalen, 1982). Human aggression is often associated with com-
plex interpersonal interactions, and the resident–intruder interaction
model may be relevant to predict what drugs may do in humans. The
resident–intruder paradigm is a widely used model in psychophar-
macology and employs the resident animal's response to a conspecific
intruder (Koolhaas, Schuurman, & Wiepkema, 1980; Miczek, 1974).
In this paradigm, a male rat or mice is housed with a female, a situa-
tion resembling the natural situation in which animals establish and
defend territories. When resident or territorial males meet an unfa-
miliar male intruder in their territory, heavy fighting may ensue, con-
sidered natural fighting (Miczek, 1979). Aggressive behavior in this
situation may consist of patrolling, approach, investigation, threats,
fighting, chasing, and dominant posturing (Koolhaas et al., 1980).
The nature of such interactions between an attacking resident and
an opponent varies with the quality of the intruder, especially age
and hormonal status, and the resident's experience (Koolhaas et al.,
1980). The types of behaviors displayed by the resident toward the
intruder are not random but follow certain rules, a strong indicator
of the neural substrates involved (Adams, 1979; Koolhaas et al.,
1980; Olivier et al., 1984). The resident–intruder model differs both
from isolation induced aggression in mice because there is no isola-
tion, which may lead to behavioral abnormalities (Valzelli, 1973).
Moreover, resident–intruder paradigms have a very wide species
generality including humans (Miczek, 1979). This model discrimi-
nates effectively the quality and behavioral mechanisms of action of
several drugs with proaggressive and anti-aggressive actions (Mos,
Olivier, & Tulp, 1992). Both proaggressive (alcohol and benzodiaze-
pines) and anti-aggressive effects of psychoactive drugs are highly
similar in rodents and humans (Olivier et al., 1984). Benzodiazepines
at low doses enhance aggression, whereas at higher doses they clearly
cause ataxia, which interferes with behavioral performance (Olivier
et al., 1984). Neuroleptics, like psychostimulants, alter the display of
agonistic behavior although in different ways. Serenics display a
highly specific anti-aggressive profile without interfering with other
behavioral functions (Mos et al., 1992; Olivier et al., 1984).
4.3. Offensive behavior induced by electrical brain stimulation
This offensive behavior is similar to that of offensive territorial males
and can be elicited by electrical stimulation in the hypothalamus of rats
200 S. Umukoro et al. / Aggression and Violent Behavior 18 (2013) 195–203
(Kruk, Van der Poel, & De Vos-Frerichs, 1979). Stimulation of the hypo-
thalamus is accompanied by an increase in levels of stress hormones (ad-
renocorticotropic hormone, corticosterone, and prolactin) and not
caused by the stress of fighting (Kruk et al., 1998). This behavior is read-
ily reproduced under controlled circumstances, thereby meeting an im-
portant requirement for a model to study aggression. Depending on
the stimulus intensity, extreme forms of offensive attack and severe
damage to the opponent can be produced (Kruk et al., 1979). In addition
to aggressive behavior, stimulation in this area of the hypothalamus also
stimulates other behaviors, including locomotion and teeth chattering
(Van der Poel et al., 1982), thereby allowing for the determination of
the specificity of drug action (Koolhaas, 1978; Kruk et al., 1979). In this
paradigm, the effects of drugs are measured by the changes in the cur-
rent thresholds required to evoke the respective behavior (Van der
Poel et al., 1982). Increases in the current thresholds for aggression indi-
cate anti-aggressive effects, considered specific if simultaneously the
drug does not affect thresholds for locomotion (Siegel et al., 1999). This
hypothalamic-induced aggression model is highly relevant for modeling
certain kinds of human aggression (Koolhaas, 1978; Kruk et al., 1979). By
directly stimulating neural substrates in the brain involved in offensive
aggression, this model has great potential to predict violent and patho-
logic aggression in humans (Siegel et al., 1999). In contrast to the more
natural models (isolation-induced, resident–intruder, maternal aggres-
sion), this model is not sensitive to certain intervening variables present
in the other paradigms (anxiety, fear, sedation, and motor and sensory
disturbances) and directly reflects anti-aggressive properties of drugs
(Siegel et al., 1999).
4.4. Maternal aggression
Although aggression is often considered a male-related phenome-
non, females can be quite aggressive under certain conditions, such as
in hypothalamically induced aggression in rats (Kruk et al., 1984) and
maternal aggression in several rodent species (Mos et al., 1987). The
use of a female aggression paradigm to model human aggression is
quite uncommon in psychopharmacology. The maternal aggression
has clear neural and hormonal determinants and is highly purposeful,
providing protection to the offspring. The maternal aggression para-
digm is based on the finding that a lactating female rat or mouse
with pups exhibits offensive behaviors toward a wide variety of in-
truders (Mos et al., 1987). This behavior is most pronounced during
the first part of the lactating period (Erskine, Barfield, & Goldman,
1978). The critical stimulus depends on the proximity of some threat-
ening object to the female's young ones (Moyer, 1968). However, the
behavior of the lactating female toward the intruder is clearly
self-initiated, proactive, and not necessarily reactive to any threat ini-
tiated by the intruder. Although the paradigm is labor intensive and
needs extensive planning, several psychoactive drugs have been test-
ed in it and have led to a model with a comparable predictive validity
as the male offensive paradigms in rodents (Erskine et al., 1978). Al-
though the patterns of the aggressive behavior of the attacking female
are different from male aggression, the effects of several classes of
drugs were shown to be similar to those found in the male paradigms
(Erskine et al., 1978).
5. Animal models of defensive behaviors
Defensive behaviors are forms of agonistic behavior, which are char-
acterized by submission, flight, and similar reactive behaviors. Fighting,
when it occurs in a defensive animal, is merely a reaction to an attack.
The defensive behaviors such as flight or submission are apparently
intended to escape from or prevent further agonistic interactions
(Koolhaas et al., 1980). Some of the drugs such as the neuroleptics
with anti-offensive activity are known to impair the defensive and flight
reactions of the animals (Koolhaas et al., 1980).
5.1. Defensive behavior in resident–intruder paradigm
The behavior of an intruder in the resident–intruder or maternal
aggression is a more natural model for assessing effects of drugs on
defensive behavior. Defending animals in these paradigms use special
tactics to protect the more vulnerable parts of their bodies (Blanchard
et al., 1998; Olivier et al., 1994). In unconstrained conditions, animals
on the defense usually flee from the territory of the residential male or
lactating female, but when this is impossible, as in laboratory conditions,
they defend themselves by flight, crouching, upright defensive postures,
emission of ultrasounds, and submissive postures (Koolhaas et al., 1980).
Generally, these behaviors are aimed at protecting the back, the area
where most wounds are inflicted by attacking rodents (Koolhaas et al.,
1980).
Several drugs (neuroleptics, alcohol, benzodiazepines, or
psychostimulants) that influence the sensory or motor capabilities
of the intruder lead to changes in the defense or flight responses of
the animals (Blanchard et al., 1998). Amphetamine enhances flight
while haloperidol impairs defense or flight capability (Olivier et al.,
1994). Serenics do not affect the defense or flight capabilities of the
intruders, an effect in line with their specific anti-offensive qualities
(Blanchard et al., 1998; Olivier et al., 1994). Pain or shock-induced
defensive behavior is another paradigm used to study the effects of
drugs on defense or flight capability of the animals. However, the be-
havior of the animal can be masked by analgesic drugs in this model
(Olivier et al., 1994). A useful application of foot shock-induced de-
fense behavior is to determine specificity of anti-aggressive agents
(Olivier et al., 1994). Neuroleptics and benzodiazepines inhibit foot
shock-induced behavior due to muscle-relaxing effects (Olivier et al.,
1994). Serenics (eltoprazine, fluprazine, and others) do not inhibit
this foot shock-induced behavior, indicating selective anti-offensive
activity.
6. Limits to animal models
Although the use of animal models has shed some light on behav-
ioral and neurobiological mechanisms of aggression, it is still difficult
to relate these mechanisms to human violence. Fighting in animals,
for example, consists of combinations of biting, wrestling and chasing,
whereas aggression in humans can take both physical and verbal
forms (Nelson & Trainor, 2007). Thus, this diversity tends to limit di-
rect comparisons between species in components of aggression. An-
other major problem with animal models is that most aggression
tests only assess the quantitative aspects of the aggressive encoun-
ters. Thus, better aggression tests are needed to assess the quality as
well as the quantity of aggression, and to translate it onto human ag-
gressive acts. Further, the studies of aggression in animals are
conducted under controlled settings, thereby eliminating the varia-
tion in environmental factors that might have crucial effects on the
behavior.
7. Pharmacological treatment of aggression
The major goal of aggression research is to develop
pharmacotherapeutic agents that can be used to control human aggres-
sion and violence without impairing other behaviors. These research ef-
forts are yet to yield specific compounds that can selectively reduce
aggression in humans. The first attempt toward the treatment of ag-
gressive behavior began in the mid-1970s with the use of lithium car-
bonate in prison inmates (Dostal & Zvolsky, 1970; Sheard, Marini,
Bridges, & Wagner, 1976). Lithium carbonate was shown to reduce
impulsive aggression to extremely low levels during the course of treat-
ment (Sheard et al., 1976). The mechanism by which lithium carbonate
reduces aggression still remains unknown, but may involve enhance-
ment of 5-HT neurotransmission and a dampening of catecholaminer-
gic function (Campbell et al., 1995; Soares & Gershon, 1998). The
 S. Umukoro et al. / Aggression and Violent Behavior 18 (2013) 195–203
current pharmacological agents used in the treatment of aggressive be-
havior or violent outbursts target various neural mechanisms including
dopamine receptors, the serotonin transporter, the beta-adrenergic re-
ceptor and GABAA receptors (Miczek et al., 2002). Although these
agents reduce aggression, they also interfere with other functions;
therefore there is a need for improved and more selective therapies
(Barrett, Edinger, & Siegel, 1990; Olivier et al., 1995; Buckley, 1999).
Dopamine receptor antagonists, such as chlorpromazine and haloper-
idol, have been used effectively for decades to treat aggressive patients,
especially those with psychotic disorder (Olivier et al., 1990). The use of
antipsychotics in the treatment of aggression is largely aimed at sedating
patients with psychosis or to reduce the psychotic thinking that may trig-
ger aggressive behavior. The propensity to cause sensorimotor perfor-
mance or catalepsy has reduced the clinical utility of antipsychotics for
long-term treatment of aggression (Olivier et al., 1990; Rabinowitz,
Avnon, & Rosenberg, 1996). These drugs also affect the defense or flight
capabilities of the organisms, which further limit their usefulness in ag-
gression (Olivier et al., 1990). Although many atypical antipsychotics ex-
hibit low tendency to cause sensorimotor performance, they also
produce other unwanted side effects (Olivier et al., 1990). Drugs like bar-
biturates and benzodiazepines, which act through potentiation of GABA
inhibitory neurotransmission, produce decreases in aggressive behavior,
however, at high doses (Olivier et al., 1990). The anti-aggressive effect of
these drugs is due to sedation or muscle relaxation (de Almeida et al.,
2005; Navarro et al., 2004). The defense or flight capabilities of the organ-
isms, is also impaired by these GABAmimetics, which further limit their
use in aggression (Olivier et al., 1990).
The role of the central noradrenergic system in facilitation of
aggression (Nelson & Trainor, 2007) suggests that agents with adren-
ergic blocking property should exhibit anti-aggressive activity. In-
deed, adrenergic receptor blockers have been found effective in
reducing aggressive behavior in patients with organic brain syn-
dromes or chronic psychosis (Haller et al., 1998; Nelson & Trainor,
2007). Both propranolol and nadolol, which are beta adrenergic re-
ceptor antagonists, reduced aggressive behavior in chronic psychiat-
ric inpatients, independent of psychotic symptoms (Haller et al.,
1998). However, the uses of these medications are limited by the
side effects of hypotension and bradycardia (Nelson & Trainor, 2007).
Pharmacotherapeutics that may be more relevant in managing violent
and aggressive individuals are those that specifically target 5-HT signaling
mechanisms either through inhibition of 5-HT reuptake or modulation of
5-HT receptor systems (Coccaro, Kavoussi, & Hauger, 1997). The rationale
to manage aggressive patients with 5-HT-enhancing agents is rooted in
the consistent findings of an inverse relationship between 5-HT and ag-
gression. Thus, the therapeutic strategies have been aimed toward en-
hancing 5-HT neurotransmission to correct or compensate for the
putative deficiency (Coccaro & Kavoussi, 1997). Both preclinical and clin-
ical studies have documented the efficacy of these agents, specifically
with respect to the 5-HT selective reuptake inhibitors (SSRIs) in aggres-
sion (Cleare & Bond, 2000; Fuller, 1996). SSRIs have been shown to reduce
verbal and physical aggression in patients with borderline personality dis-
order (Coccaro et al., 1997; Fuller, 1996). The enhancement of central
5-HT function by the SSURI is presumed to underlie their anti-aggressive
effect in these patients (Coccaro et al., 1997; Fuller, 1996). However, the
SSURIs cannot selectively reduce aggression, without affecting other be-
haviors or causing serious unwanted side effects (Cleare & Bond, 2000;
Fuller, 1996).
The pharmacological approach to the treatment of aggressive
behavior or violent outbursts demands the use of agents that can inter-
act with a subset of 5-HT receptors that are critically involved in the
mediation of aggression. Current research effort is now focused on the
development of agents that selectively reduce aggression by targeting
specific subtypes of 5-HT especially 5-HT1A/B receptor and 5-HT2A/C
receptors (Cleare & Bond, 2000). The 5-HT1A agonists have been
shown to exert potent anti-aggressive activity without interfering
with other behavioral functions (Summers et al., 2005). The 5-HT1A/B
201
agonists, such as eltoprazine, zolmitriptan, anpirtoline, 5-methoxy-N,
N-dimethyltryptamine, ipsapirone, and buspirone significantly reduce
aggressive behaviors in a hostile confrontation (Bell & Hobson, 1994;
Olivier et al., 1989). The pharmacological mechanism of action of these
serenic drugs is generally explained by changes in 5-HT neuron function
that heighten the effectiveness of serotonergic signaling at their postsyn-
aptic receptor targets. These drugs also reduce the escalated aggression
that often follows alcohol consumption, frustration, and social instigation
(de Almeida et al., 2001; Fish, Faccidomo, & Miczek, 1999). The behavior-
ally selective profile of these agents suggests that 5-HT1B/A agonists might
be attractive compounds for the control of aggression and violence (de
Almeida et al., 2005; Mendoza et al., 1999; Sanchez et al., 1993; White
et al., 1991). Although 5-HT2 receptor agonists caused a decrease in ag-
gressive responses, they also elicit a characteristic side effect of 5-HT
stimulation termed “wet dog shaking” (Sloviter et al., 1978). Antagonism
of 5-HT2 receptors decreased aggression in animal models, and this effect
may explain the ability of the newer antipsychotic agents (which, unlike
the older generation, block 5-HT2 receptors) to produce a reduction in ag-
gression and agitation (Buckley et al., 1995). Studies suggest that the
overall frequency of assaults, use of seclusion, mechanical restraint, and
chemical restraint in patients with schizophrenia who are treated with
clozapine are reduced over traditional neuroleptics (Ratey et al., 1993).
However, the efficacy and tolerability of selective 5-HT2 receptor antago-
nists on aggression are yet to be established.
8. Conclusion and challenges for future research
Although several mechanisms are involved in the expression of
aggression, it is imperative that the precise neurochemical vulnerabil-
ities be clearly defined and understood. It is a challenge for future re-
search to elucidate how precisely these mechanisms interact to
contribute to aggressive behavior. Further, animal studies of aggres-
sion typically measure aggressive behavior under a controlled single
set of environmental conditions. However, expression of aggression
in humans is subject to fluctuating physical and social environments.
Thus, better aggression tests are necessary to assess the quality as
well as the quantity of aggression in animals, and how to relate ani-
mal data to human aggression. Moreover, the continued discovery
of more 5-HT receptor subtypes indicates that further studies may
be needed to clearly define the specific roles of the various receptors
and their interactions in aggression. The development of more specif-
ic 5-HT-receptor agonists and antagonists will also aid in the under-
standing of the basic mechanisms that underlie aggression. The
major goal of aggression research is to develop interventions that
could control human aggression. And current research efforts are di-
rected toward the use of agents that can selectively reduce aggression
by targeting specific subtypes of 5-HT receptors that are critical in the
mediation of violent behavior.
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