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Aggressive behavior and three neurotransmitters: Dopamine, GABA, and serotonin—A review of the last 10 years

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Abstract

Aggressive behavior has received considerable research attention for more than five decades. Although extensively studied, the mechanisms involved in both functional and pathological aggression are still far from elucidated. The regulation of aggression by a wide spectrum of neurotransmitters is well known. Serotonin has shown both inhibitory and stimulating effects on aggressive behavior, depending on the brain region measured and specific receptors where it acts. Dopamine and the mesocorticolimbic system associated with reward seeking behavior are also associated with aggression. Dopamine can sometimes enhance aggression and sometimes reduce the impulsivity that might lead to abnormal aggression. γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter, and its relationship with aggressive behavior is extremely complex and highly associated with serotonin. This review focuses on summarizing the roles played by these three neurotransmitters (serotonin, dopamine, and GABA) in aggressive behavior and analyzing aggressive behavior from both neuropsychology and interdisciplinary perspectives.
Psychology & Neuroscience, 2014, 7, 4, 601-607
DOI: 10.3922/j.psns.2014.4.20
Aggressive behavior and three neurotransmitters: dopamine,
GABA, and serotonin—a review of the last 10 years
Rodrigo Narvaes and Rosa Maria Martins de Almeida
Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Abstract
Aggressive behavior has received considerable research attention for more than ve decades. Although extensively studied, the
mechanisms involved in both functional and pathological aggression are still far from elucidated. The regulation of aggression by
a wide spectrum of neurotransmitters is well known. Serotonin has shown both inhibitory and stimulating effects on aggressive
behavior, depending on the brain region measured and specic receptors where it acts. Dopamine and the mesocorticolimbic
system associated with reward seeking behavior are also associated with aggression. Dopamine can sometimes enhance
aggression and sometimes reduce the impulsivity that might lead to abnormal aggression. γ-Aminobutyric acid (GABA) is the
main inhibitory neurotransmitter, and its relationship with aggressive behavior is extremely complex and highly associated with
serotonin. This review focuses on summarizing the roles played by these three neurotransmitters (serotonin, dopamine, and
GABA) in aggressive behavior and analyzing aggressive behavior from both neuropsychology and interdisciplinary perspectives.
Keywords: aggression, dopamine, GABA, humans, mice, prefrontal cortex, raphe nuclei, serotonin.
Received 20 December 2013; received in revised form 03 June 2014; accepted 05 June 2014. Available online 16 December 2014.
Rodrigo Narvaes and Rosa Maria Martins de Almeida,
Laboratório de Psicologia Experimental, Neurociências e
Comportamento, Instituto de Psicologia do Desenvolvimento
e da Personalidade, Universidade Federal do Rio Grande do
Sul (UFRGS), Porto Alegre, RS, Brazil. Rosa Maria Martins
de Almeida, Bolsista de Produtividade CNPq nível 1D.
Correspondence regarding this article should be directed
to: Rosa Maria Martins de Almeida, Instituto de Psicologia,
Universidade Federal do Rio Grande do Sul, Rua Ramiro
Barcelos, 2600, Bairro Santa Cecília, Porto Alegre, RS, CEP
90035-003, Brasil. Phone: +55 (51) 3308-5066. Fax: +55
(51) 3308-5470. E-mail: rosa_almeida@yahoo.com or rosa.
almeida@ufrgs.br
Introduction
Aggressive behavior has received considerable
research attention for more than ve decades (Ferrari,
Palanza, Parmigiani, de Almeida, & Miczek, 2005), and
the amount of data available on this subject has seen
substantial growth in the last 10 years. Aggression is a
complex social behavior that evolved within the context
of defending or obtaining resources (Nelson & Trainor,
2007) and is a well known part of several mating rituals
in a broad variety of species. Animals show aggression
to protect themselves and their offspring from predators,
in the struggle for females and food, and to maintain
a dened hierarchy in the community (Popova, 2008).
Traditionally, it has been dened as overt behavior
that has the intention of inicting physical damage on
another individual (Soma, Scotti, Newman, Charlier,
& Demas, 2008). Two subtypes of aggression have
been identied in humans: the controlled-instrumental
subtype and the reactive-impulsive subtype. The latter
is considered impulsive (usually associated with anger),
whereas the former is considered more purposeful and
goal-oriented (Nelson & Trainor, 2007). Impulsive
aggression is a complex behavioral phenotype, and
multiple brain systems contribute to its etiology and
high comorbidity with other disorders (Seo, Patrick, &
Kennealy, 2008). Instrumental aggression, in contrast,
is highly seen in psychopathy (von Borries, Volman, de
Brujin, Bulten, Verkes, & Roelofs, 2012) and is indirect
aggression in which an individual tries to harm another
through the use of social schemes (Vaillancourt &
Sunderani, 2011). Aggressiveness per se has never been
considered abnormal, but many problems can occur
when aggressiveness is associated with a psychological
disorder (Haller & Kruk, 2006). Aggression, in fact, is a
key symptom in a numerous psychiatric disorders such
as mood disorders and personality disorders (Veenema
& Neumann, 2007). Drug abuse, schizophrenia, autism,
and bipolar disorder are just a few examples (Bronsard,
Botbol, & Tordjman, 2010; Kloke, Jansen, Heiming,
Palme, Lesch, & Sachser, 2011; Soyka, 2011; Voravka,
2013).
Several experiments with animals (Caramaschi, de
Boer, de Vries, Koolhaas, 2008a; Kloke et al., 2011;
Jansen et al., 2011) have demonstrated the possibility,
using proper protocols, to escalate normal aggressive
behavior into pathological aggressive behavior.
Narvaes and Almeida
602
Experiencing victory in conicts against other animals
can cause a “winner effect,” which can increase
aggressive behavior to pathological levels (Kloke et
al., 2011). Male rats that attack female, anesthetized,
or submissive rats are commonly used as indicators of
pathological aggression.
Recently, transgenic mice have been considered
a good alternative to the time-consuming and difcult
protocol of instigating an escalation of aggression.
Targeting specic genes is a promising way to generate
animals with much lower thresholds for aggression.
However, the differences between the neurobiological
mechanisms that govern aggressive behavior in different
species are a signicant challenge to the development
of animal models of escalated aggressive behavior
(Miczek, De Boer, & Haller, 2013).
In humans, aggressive behavior has seemed
to exponentially increase in the last few decades.
According to the World Health Organization, the
number of fatal victims in interpersonal conict in
2002 was almost twice the number of war victims
(Krug, 2002). More recent reports showed that at least
700,000 people die each year as victims of aggressive
assault (Bartolomeos, Brown, Butchart, Harvey,
Meddings, & Sminkey, 2007).
Neurotransmitters are signaling molecules in
the nervous system. Their function as signaling
molecules depends on receptors that are specic to each
neurotransmitter in the synaptic cleft. Examples include
serotonin, dopamine, γ-aminobutyric acid (GABA),
norepinephrine, and acetylcholine, among many others.
These molecules are key factors in a wide range of
behaviors. The role of neurotransmitters in aggression
is discussed below.
Several neural networks have been associated with
aggressive behavior, and studies on aggression have
been conducted in many different species including
sh (Øverli et al., 2004), lizards (Kabelik, Alix,
Burford, & Singh, 2013), song sparrows (Maddison,
Anderson, Prior, Taves, & Soma, 2012), cats (Bhatt,
Zalcman, Hassanain, & Siegel, 2005), rats, mice, and
humans. The hypothalamic-pituitary-gonadal (HPG)
axis regulates testosterone levels in the organism
(Mehta & Josephs, 2010). High testosterone levels
can decrease the activity of the medial region of the
orbitofrontal cortex (OFC) within the prefrontal cortex
(PFC) and stimulate aggressive behavior (Mehta &
Beer, 2009). One of the possible mechanisms by which
testosterone can reduce the activity of the OFC is by
regulating serotonin. Androgens have been previously
shown to downregulate serotonin receptor mRNA
expression and serotonin turnover in the medial PFC
(mPFC; Ambar & Chiavegatto, 2009). The relationship
between the levels of testosterone and cortisol, a
product of the hypothalamic-pituitary-adrenal (HPA)
axis, known for being physiologically antagonistic to
the HPG axis, was found to be associated with the way
aggression is expressed (Montoya, Terburg, Bos, &
van Honk, 2012). Psychopaths, for example, usually
have a higher testosterone/cortisol ratio than normal
individuals (Glenn, Raine, Schug, Gao, & Granger,
2011). The relationship between these hormones and
the way they regulate aggressive behavior support a
dual-hormone hypothesis (Mehta & Josephs, 2010) in
which high testosterone/cortisol ratios lead to higher
levels of aggression, and low testosterone/cortisol
levels lead to evasion of the ght response (Montoya
et al., 2012).
The complexity of aggressive behavior, contradictory
data on neurotransmitter function under different
conditions and in different individuals and brain regions,
and various expressions of aggressive behavior in different
species and genders reinforce the need for a review of the
current knowledge.
Objectives
This systematic review sought to analyze the
inuence of three neurotransmitters (dopamine, GABA,
and serotonin) on aggressive behavior.
Data collection
The data were collected by searching keywords
in the scientic databases PubMed (2003-2013) and
Web of Knowledge (2003-2013). The keywords were
aggressiveness, dopamine, GABA, humans, rats,
prefrontal cortex, raphé nuclei, and serotonin. The
keywords were combined in groups (up to three words
per group). The keyword “aggressiveness” was used in
every search to retrieve results related to the subject.
The search results were judged by a researcher with
experience in the eld and then selected or discarded,
as described in Figure 1. Of the 198 articles found,
19 were discarded because they were not directly
related to the subject. From the remaining 182, 61
were used in this review. The criteria that were used to
select the articles that would be used were relevance,
year of publication, and distinctiveness. Articles that
contained similar information to those in other papers
had a lower priority than those with new or seemingly
contradictory data.
Search for articles in the scientific
databases PubMed (2003-2013) and Web
of Knowledge (2003-2013) using the
keywords (aggressiveness + one or two
of the other keywords)
198 articles were found
19 articles were
discarded
179 articles were accepted
58 articles were used in this review
Figure 1. Flowchart of the methodology used in this review.
Aggressive behavior and three neurotransmitters 603
Serotonin
In the last few decades, the recognition of serotonin
(5-hydroxytryptamine [5-HT]) as a key neurotransmitter
related to aggressive behavior has grown. Serotonergic
neurons originate from raphé nuclei in the brain stem.
The axons of serotonergic neurons in raphé nuclei in
the midbrain reach almost every structure in the brain
(Celada, Puig, & Artigas, 2013). The relationship between
serotonin and aggression is extremely complex. Different
neural pathways can present different reactions to the
same pharmacological manipulation depending on the
receptor subtypes that are present in the pathway. There
are currently seven known families of 5-HT receptors:
5-HT1, 5-HT2, 5-HT3, 5-HT4, 5HT5, 5-HT6, and 5-HT7.
Serotonin and male aggression
Generally, serotonin has an inhibitory action on
aggressive behavior (Carrillo, Ricci, Coppersmith, &
Melloni, 2009). However, aggressive behavior in its
functional form, in which it fullls a communicative
function, is positively related to serotonin levels
(Kulikov, Osipova, Naumenko, Terenina, Mormède, &
Popova, 2012), whereas pathological forms of aggression
are usually inhibited by serotonin (De Boer, Caramaschi,
Natarajan, & Koolhaas, 2009). Heightened serotonin
activity through the elevation of serotonin precursor
levels, serotonin reuptake inhibition, or 5-HT1A receptor
agonism is known to reduce aggressive behavior (Nelson
& Trainor, 2007). 5-HT1B receptors are mostly located
presynaptically on serotonergic neuron terminals in the
raphé nuclei to modulate the release of serotonin (Suzuki,
Han, & Lucas, 2010). The activation of 5-HT1B receptors
inhibits aggressive behavior, independent of serotonin
levels. Presumably, the behavioral effects regulated
by 5-HT1B receptors reect the modulation of systems
associated with other neurotransmitters (Nelson &
Trainor, 2007).
Studies have demonstrated that 5-HT1A receptor
agonists potently inhibit aggressive behavior,
particularly in animals with high or escalated levels of
aggression. Serotonin levels in the PFC in aggressive
mice were lower in animals that exhibited higher
sensitivity of 5-HT1A autoreceptors (Caramaschi,
de Boer, & Koolhaas, 2007). This nding suggests
that the inhibition of serotonergic neurons in the
raphé nuclei through these autoreceptors may be a
marker in individuals with high levels of aggression.
Therefore, pharmacological manipulations that target
these autoreceptors could be used to lower aggressive
behavior. Data that showed that serotonin inhibits
aggression eventually led to the “serotonin deciency
hypothesis.”
One particularly interesting nding is that serotonin
not only regulates the levels of aggressive behavior
but also regulates the reaction to aggressive behavior.
A study with humans showed that serotonin levels
were associated with unfairness in an application of
the Ultimatum Game, a well-known protocol that
assesses aggressive behavior (Crockett, Clark, Tabibnia,
Lieberman, & Robbins, 2008). Whenever the levels of
serotonin were lower, the individuals who received an
unfair offer were signicantly more willing to retaliate,
although they reported no mood alteration or changes in
judging the fairness of the offer. These data also support
the involvement of serotonin in defensive aggression.
In fact, the reduction of defensive aggression
levels over generations leads to abnormal serotonin
metabolism. The animal model that was used for this
experiment was the silver fox. Foxes that were selected
for low levels of defensive aggressive behavior expressed
much higher serotonin levels in specic brain regions
(Popova, 2004). Differences in serotonin levels in the
PFC are also considered one of the key factors involved
in highly aggressive behavior in some mouse lines, such
as the Short-Attack-Latency (SAL) and Long-Attack-
Latency (LAL) lines (Caramaschi, de Boer, & Koolhaas,
2008b). These lineages are used as a model in studies of
aggression because of their high (SAL) and low (LAL)
levels of innate aggression. Veenema and Neumann
(2007) reported that SAL mice had a higher level of
postsynaptic 5HT1A receptors in the hippocampus and
higher binding capacity than LAL mice, accompanied
by higher serotonin responsiveness, but no difference
was found in presynaptic 5HT1A autoreceptor levels in
the raphé nuclei. This is not an isolated case of serotonin
stimulating aggressive behavior. Olivier (2004)
provided both published and unpublished evidence that
5HT1B receptors can actually induce aggressive behavior
instead of inhibiting it. Despite the extensive amount of
research on serotonin’s relationship with aggression, its
precise role is still unclear.
Serotonin and female aggression
Although females are usually not used as models
of aggression, maternal postpartum aggressive behavior
is one way to induce an escalated state of aggression
to generate data on aggressive behavior in females. Da
Veiga, Miczek, Lucion, and de Almeida (2011) used
a protocol of social instigation in postpartum females
to induce aggressive behavior using selective and
full agonists of 5HT1A and 5HT1B receptors (8-OH-
DPAT and CP-93,129, respectively). 8-OH-DPAT is
a well-known and broadly used agonist that potently
reduces aggressive behavior, despite being able to
induce hypothermia (de Boer & Koolhaas, 2005). CP-
93,129 is also used to reduce aggressive behavior and
also heightens non-aggressive, non-social exploratory
behavior in male mice (de Boer & Koolhaas, 2005) and
snifing and rearing behavior in postpartum female
mice (da Veiga, Miczek, Lucion, & de Almeida, 2007).
Surprisingly, 8-OH-DPAT, when injected in the dorsal
raphé nuclei (DRN), actually increases the levels of
aggressive behavior in postpartum females (da Veiga et
al., 2011). This nding demonstrates the complexity of
the serotonergic system and how it works differently in
different genders. Moreover, serotonin levels are related
Narvaes and Almeida
604
to the levels of other neurotransmitters, such as GABA,
which will be discussed later.
Dopamine
3-Hidroxy thiamine, or dopamine, is a
neurotransmitter that belongs to the family of
catecholamines (Hansen & Manahan-Vaughan, 2012).
The dopaminergic system is involved in movement
control, the reward system (Arias-Carrión, Stamelou,
Murillo-Rodriguéz, Menéndez-González, & Pöppel,
2010), and the persistence of long-term memory (Rossato,
Bevilaqua, Izquierdo, Medina, & Cammarota, 2009).
Although dopaminergic neurons represent less than 1%
of the total neuron population, they have a profound effect
on brain function (Arias-Carrión & Pöppel, 2007). The
neural projections of the dopaminergic system include
efferents from the ventral tegmental area to the nucleus
accumbens and PFC and efferents from the substantia
nigra (Arias-Carrión & Pöppel, 2007). There are ve
different dopamine receptors: D1, D2, D3, D4, and D5.
Dopamine’s role in aggressive behavior is not
yet precisely known. The dopaminergic system is
activated when an offensive animal meets a defensive
one (Ferrari, van Erp, Tornatzky, & Miczek, 2003).
Whenever a resident mouse encountered an aggressive
intruder mouse at a regular interval, both dopamine
and serotonin levels increased in anticipation of the
confrontation. Both neurotransmitters are involved
not only in aggressive behavior but also in coping
with stress. Both pleasant and stressful events activate
the mesocorticolimbic dopamine system (Miczek,
Faccidomo, de Almeida, Bannai, Fish, & Debold,
2004). Growing evidence suggests the participation
of dopamine in aggressive behavior. The dopamine
transporter is responsible for controlling extracellular
dopamine levels, and dopamine transporter knockout
mice exhibit higher expression levels of D1 and D2
receptors, higher aggressiveness, higher extracellular
dopamine levels, and lower concentrations of D1 and
D2 receptors (Rodriguiz, Chu, Caron, & Wetsel, 2004).
These are surprising data because D1 and D2 receptor
antagonists inhibit aggressive behavior (Nelson &
Trainor, 2007). One well-known example of such
an inhibitory capacity is the D2 receptor antagonist
risperidone, which is commonly used to reduce
aggressive behavior associated with arousal and stress
(Nelson & Trainor, 2007). The use of risperidone is
common in patients with autism and schizophrenia, in
which both conditions present with abnormal aggressive
behavior (Bronsard et al., 2010; Soyka, Graz, Bottlender,
Dirschedl, & Schoech, 2007).
Dopamine’s involvement in the regulation of
aggressive behavior might be associated with competitive
motivation. Aggressive behavior arises when conict
occurs between two individuals, and interpretation
of the confrontation as a ght for resources makes
dopamine’s involvement quite predictable because
of its role in the reward system (Arriás-Carrion et al.,
2010). Moreover, dopamine levels are also associated
with risk-taking, in which risk evaluation is based on the
size of the reward that is implied in the risk, making its
role in aggression even more important. An experiment
performed by Riba, Krämer, Heldmann, Richter, and
Münte (2008) highlights this point. Pramipexole is a
D2/D3 receptor agonist that is reported to be associated
with gambling addiction when used to treat Parkinson’s
disease. Pramipexole was administered in healthy
patients during a simple lottery task as part of a placebo-
controlled, double-blind study in an attempt to simulate
the effects of this dopamine agonist in patients with
Parkinson’s disease, which is known to present with
lower dopamine levels in nigrostriatal pathways. The
results showed a signicant increase in the number of
risky decisions made by the patients, associated with
lower activation of dopamine systems when these
decisions were followed by gains that exceeded the
patient’s expectations. This reduction of sensitivity to
reward might explain why the patients were always
making riskier decision. According to these authors,
this blunting of the reward system leads to the pursuit of
even higher rewards because the patients do not feel as
rewarded as a normal person would. However, patients
who were treated with L-3,4-dihydroxyphenylalanine
(L-DOPA), a precursor of dopamine, did not show the
same pattern. This difference illustrates the heterogeneity
of functions performed by different types of dopamine
receptors and complexity of the underlying mechanisms
of dopamine regulation of the reward system.
γ-Aminobutyric Acid
GABA and male aggression
GABA is well known as the main inhibitory
neurotransmitter in the mammalian brain. It is an
extremely anciently derived molecule that is also found
in plants, fungi, bacteria, cnidarians, and insects. It
exerts its inhibitory actions even in organisms with the
simplest of nervous systems, hydrozoans (Gou, Wang,
& Wang, 2012). It is synthesized from its precursor,
L-glutamate, through a process of decarboxylation via
the enzyme glutamate decarboxylase (Wassef, Baker, &
Kochan, 2003). GABAergic neurons project to virtually
all regions of the brain and exert potent regulatory
actions on several brain mechanisms. There are three
types of GABA receptors: GABAA and GABAC are
ionotropic, and GABAB is metabotropic and coupled to
a G-protein. GABAA receptors are the best characterized
of the three subtypes (Wassef et al., 2003) and are
widely found in the central nervous system, both pre-
and postsynaptically (Sankar, 2012).
GABAs involvement in aggressive behavior is
mostly associated with its inhibitory action, but some
ndings have been contradictory. Studies that directly
manipulate GABA levels point to an inverse correlation
with aggressive behavior (Miczek, Fish, & De Bold,
2003). However, studies that used positive allosteric
modulators of GABA, such as alcohol, have reported
Aggressive behavior and three neurotransmitters 605
enhanced aggressive behavior (de Almeida, Ferrari,
Parmigiani, & Miczek, 2005). This increase might be
related to the activity of GABAA receptors in the DRN,
as discussed later.
Interestingly, although GABAA receptor activation
is associated with a decrease in aggressive behavior,
positive modulators can enhance aggression. GABAB
receptors, in contrast, are directly related to escalated
aggressive behavior. Takahashi, Kwa, DeBold, and
Miczek (2010a) showed that pharmacological activation
of GABAB receptors in the DRN play an important role
in the escalation of aggressive behavior. This nding
also sheds light on the interaction between GABA and
serotonin because serotonergic neurons in the raphé
nuclei are responsible for the regulation of serotonin
levels. The many nuances of escalated aggressive
behavior are being unveiled, and accumulating data on
each isolated neurotransmitter and how neurotransmitters
regulate each other will aid the discovery of treatments
for pathological aggressive behavior.
GABA and female aggression
GABAA receptors are associated with offspring
protection in females, and their localization in the
lateral septum is involved in female aggression (Lee &
Gammie, 2009). In this study, benzodiazepines which,
like alcohol, are positive allosteric regulators of GABA
activity, increased aggressive behavior in postpartum
females. Peripheral administration of the GABAA agonist
chlordiazepoxide also enhanced aggression in females,
although GABAA receptors are traditionally associated
with the suppression of aggressive behavior. One year
later, the same authors (Lee & Gammie, 2010) published
a study that investigated the caudal periaqueductal gray
and found a different response prole. Chlordiazepoxide
did not enhance aggressive behavior, whereas the
GABAA receptor antagonist bicuculline signicantly
reduced aggressiveness in females but had no effect
when injected into the aqueductal gray. Further research
is still necessary to elucidate GABAs complex activity
in aggressive behavior, but GABA receptors are already
a valid therapeutic target for the regulation of aggression.
Neurotransmitter System Integration
As cited above, GABA is well known to regulate
serotonin levels because of high receptor expression in
the DRN (Takahashi et al., 2010a; Takahashi, Shimamoto,
Boyson, De Bold, & Miczek, 2010b). Both GABAA
and GABAB receptors are involved in the regulation
of serotonin levels. The activation of GABAergic
receptors on serotonergic neurons can lead to higher
serotonin levels in the mPFC and, therefore, can induce
aggression. Notably, however, GABA receptors in the
medial raphé nuclei (MRN) have no escalating effect on
aggressive behavior, showing that serotonin neurons in
the MRN and DRN play differential roles in aggressive
behavior. This might be attributable to the different
areas where these regions project their efferents. The
MRN is mostly related to the dorsal hippocampus and
medial septal nucleus, whereas the DRN projects to
the dorsal striatum, ventral hippocampus, amygdala,
nucleus accumbens, and cerebral cortex (Mokler, Dugal,
Hoffman, & Morgane, 2009).
The extreme complexity of the activity of these
neurotransmitters is one of the major complications
in the study of aggressive behavior, and establishing
causal relationships between the activities of
these neurotransmitters has been difcult. Other
neurotransmitters or hormones might also be involved.
Higher levels of cortisol, for example, are associated
with aggression but only when present in males with high
testosterone levels (Montoya et al., 2012). Nitric oxide
is associated with lower pain sensitivity, and nitric oxide
synthase knockout animals show an increased duration
of aggressive behavior (Nelson, Trainor, Chiavegatto,
& Demas, 2006). There are many examples of how
different neurotransmitters are involved in aggression,
but their roles are not precisely known across the many
animal models that are utilized to evaluate aggressive
behavior. Understanding aggressive behavior in animals
is still important because they help us comprehend the
evolution of aggressiveness and how individuals of a
given species react to predators or competitors before
reintroducing them into the wild. The many facets of how
the understanding of aggressive behavior can benet
science are usually obfuscated by the “therapeutical
use”, but that is a misunderstanding of the potential
applications for aggression studies.
Perspectives
Several new methodologies can be used to improve
our knowledge on how aggressive behavior works.
Epigenetics is a rising star, and research in this area
has great potential to shed light on how environmental
changes regulate and stimulate aggressive behavior. One
might investigate, for example, the genes associated
with serotonin, dopamine, or GABA receptors or their
transporters and how their methylation patterns change
when an animal is exposed to aggressive encounters.
These changes may be a key factor in explaining
enhanced aggressive behavior and discovering new
targets that both treat and induce aggression. Challis,
Beck, and Berton (2014) optogenetically modulated
serotonergic neurons in the DRN to interfere with
socioaffective choices after a protocol of social
defeat. The specicity of optogenetic methods may be
useful to ll some gaps in the current knowledge of
serotonergic, dopaminergic, and GABAergic neurons
and their interregulation. Aggressive behavior should
be viewed not only as a health issue but also from
an environmental perspective. The reintegration of
animals into their natural environment after trauma
or isolation might represent more of a threat to the
population. To address this issue, determining how
individual differences can change the effectiveness
of a given drug can be signicantly important. This
Narvaes and Almeida
606
kind of analysis would attract substantial interest from
conservational institutions and create opportunities
for other professionals who are not directly involved
in studies of human health, such as ethologists. In the
current global conditions of weather, biodiversity,
and natural resources, boundaries need to be softened
between health research and environmental research,
and research on aggressive behavior may provide a
major opportunity.
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... По сравнению с многочисленными исследованиями роли серотониновой нейротрансмиссии в развитии и регуляции АП, дофаминергическая система остается менее изученной. Хотя дофаминовые нейроны составляют менее 1% от общей популяции нейронов в головном мозге, это не умаляет значимость данной моноаминергической системы [14]. Существует гипотеза о значительном влиянии дофамина на формирование АП. ...
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This scientific review highlights the results of domestic and foreign studies aimed at researching the biological aspects of failure to control aggressive impulses. We analyze the role of serotonergic, dopaminergic, noradrenergic, glutamatergic systems, and neuroendocrine mechanisms in aggression manifestation. We discuss the inconsistency of modern concepts about the neurochemical nature of aggressive behavior. The relevance of evaluating the biomarkers of public danger is substantiated. Finally, questions of psychopharmacotherapy of aggressive behavior are reviewed.
... It is still up for debate what the exact point of unbalance is. The onset and development of aggressive behavior have been related to various neurotransmitter levels, such as serotonin and dopamine (Narvaes and Martins de Almeida, 2014;Seo et al., 2008). Studies in both human and animal models have also found a connection between aggression, genetic variability, and dysregulation of multiple genes (Anholt and Mackay, 2012). ...
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Objective: To analyze the available data on the anti-anger effects of herbal medicines (HMs) as well as their underlying mechanisms in rat models. Methods: From 6 electronic databases [PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang, Oriental Medicine Advanced Searching Integrated System (OASIS), and Research Information Sharing Service (RISS)], relevant animal experiments were searched by using "anger," "rats," and "animal" as search keywords. The last search was conducted on November 22, 2019, and all experiments involving rat models of anger and treatment using HMs published until the date of the search were considered. Results: A total of 24 studies with 16 kinds of HMs were included. Most studies have used the "tail irritating method" and "social isolation and resident intruder" method to establish anger models. According to the included studies, the therapeutic mechanisms of HMs for anger regulation and important herbs by their frequency and/or preclinical evidence mainly incladed regulation of hemorheology (Bupleuri Radix, Paeoniae Radix Alba, and Glycyrrhizae Radix), regulation of sex hormones (Bupleuri Radix, Cyperi Rhizoma, and Paeoniae Radix Alba), regulation of neurotransmitters (Cyperi Rhizoma), regulation of anger-related genes (Bupleuri Radix, Glycyrrhizae Radix, and Paeoniae Radix Alba), and other effects. Overall, Liver (Gan) qi-smoothing herbs including Bupleuri Radix and Cyperi Rhizoma were the most frequently used. Conclusions: This review found the frequent methods to establish an anger model, and major mechanisms of anti-anger effects of HMs. Interestingly, some Liver qi-smoothing herbs have been frequently used to investigate the anti-anger effects of HM. These findings provide insight into the role and relevance of HMs in the field of anger management.
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Severe aggressive behavior of juvenile pufferfish affects economic efficiency and fish welfare in aquaculture. 5-HT plays an important role in regulating the aggressive behavior of fish in aquaculture environment. This study examined the effects of different concentrations (0, 0.25, 0.5, 1 mg/kg) of 8-OH-DPAT, a selective 5-HT1A receptor agonist, on the aggressive behavior of juvenile pufferfish. Forty-five minutes after drug injection, the aggressive behavior of juvenile fish was recorded for 20 min, including the latency to the first attack and the frequency of aggressive behaviors. The results showed no significant differences in the latency to the first attack of juvenile fish among treatment groups. During the first 10 min of the observation period, there was no significant difference in the total aggressive acts and locomotor activity among treatment groups. Total aggressive acts and locomotor activity were the least in the 1 mg/kg 8-OH-DPAT-treated during the 20 min observation period. Both aggressive behavior and locomotor activity were negatively correlated with 8-OH-DPAT treatment overall, respectively. The above results suggested that the serotonergic system activation had suppressive effects on aggressive behavior and locomotor activity in juvenile pufferfish.
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It has been well established that modulating serotonin (5-HT) levels in humans and animals affects perception and response to social threats, however the circuit mechanisms that control 5-HT output during social interaction are not well understood. A better understanding of these systems could provide groundwork for more precise and efficient therapeutic interventions. Here we examined the organization and plasticity of microcircuits implicated in top-down control of 5-HT neurons in the dorsal raphe nucleus (DRN) by excitatory inputs from the ventromedial prefrontal cortex (vmPFC) and their role in social approach-avoidance decisions. We did this in the context of a social defeat model that induces a long lasting form of social aversion that is reversible by antidepressants. We first used viral tracing and Cre-dependent genetic identification of vmPFC glutamatergic synapses in the DRN to determine their topographic distribution in relation to 5-HT and GABAergic subregions and found that excitatory vmPFC projections primarily localized to GABA-rich areas of the DRN. We then used optogenetics in combination with cFos mapping and slice electrophysiology to establish the functional effects of repeatedly driving vmPFC inputs in DRN. We provide the first direct evidence that vmPFC axons drive synaptic activity and immediate early gene expression in genetically identified DRN GABA neurons through an AMPA receptor-dependent mechanism. In contrast, we did not detect vmPFC-driven synaptic activity in 5-HT neurons and cFos induction in 5-HT neurons was limited. Finally we show that optogenetically increasing or decreasing excitatory vmPFC input to the DRN during sensory exposure to an aggressor's cues enhances or diminishes avoidance bias, respectively. These results clarify the functional organization of vmPFC-DRN pathways and identify GABAergic neurons as a key cellular element filtering top-down vmPFC influences on affect-regulating 5-HT output.
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