Tryptophan diet reduces aggressive behavior in male mice

Abstract

A tryptophan diet reduces aggressive behavior in different species, although some controversial findings have been reported. We studied 65 male mice divided into four groups according to increasing dosages of tryptophan (10, 20, 30, and 100 mg/kg) and a control group (vehicle). The first four groups ingested 10, 20, 30, and 100 mg/kg tryptophan together with cellulose vehicle and water by gavage before the behavioral tests that sought to record aggressive behavior. The control group received only the vehicle at the same time that the other groups received the tryptophan solutions. The results showed that low concentrations (10 and 20 mg/kg) of tryptophan decreased (p <.04) the frequency of attack bites and lateral threats (i.e., aggressive components; p <.02) after an encounter with a male intruder without altering locomotor activity. In conclusion, the low concentrations of tryptophan diminished aggressive behavior against a male intruder.

Full text

Psychology & Neuroscience, 2013, 6, 3, 397 - 401
DOI: 10.3922/j.psns.2013.3.18
Tryptophan diet reduces aggressive behavior in male mice
Julio Cesar Walz1, 2, Laura Stertz1, Adam Fijtman1, Bárbara T. M. Q. dos Santos1, and Rosa Maria
M. de Almeida1
1. Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
2. Centro Universitário Unilasalle, Canoas, RS, Brazil
Abstract
A tryptophan diet reduces aggressive behavior in different species, although some controversial findings have been reported. We
studied 65 male mice divided into four groups according to increasing dosages of tryptophan (10, 20, 30, and 100 mg/kg) and a
control group (vehicle). The first four groups ingested 10, 20, 30, and 100 mg/kg tryptophan together with cellulose vehicle and
water by gavage before the behavioral tests that sought to record aggressive behavior. The control group received only the vehicle
at the same time that the other groups received the tryptophan solutions. The results showed that low concentrations (10 and 20
mg/kg) of tryptophan decreased (p < .04) the frequency of attack bites and lateral threats (i.e., aggressive components; p < .02)
after an encounter with a male intruder without altering locomotor activity. In conclusion, the low concentrations of tryptophan
diminished aggressive behavior against a male intruder. Keywords: aggression, diet, serotonin, impulsive behavior.
Received 05 March 2013; received in revised form 25 July 2013; accepted 03 August 2013. Available online 23 December 2013.
Julio Cesar Walz, Laura Stertz, Adam Fijtman, and Bárbara T.
M. Q. dos Santos, INCT Translational Medicine & Molecular
Psychiatry Laboratory, Hospital de Clínicas de Porto Alegre,
Universidade Federal do Rio Grande do Sul, Porto Alegre,
Brazil. Rosa Maria M. de Almeida, Instituto de Psicologia do
Desenvolvimento e da Personalidade, da Universidade Federal
do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
Laboratório de Psicologia Experimental, Neurociências e
Comportamento (LPNeC), Pesquisadora de Produtividade
do CNPq. Julio Cesar Walz, Centro Universitário Unilasalle,
Canoas, RS, Brazil. Correspondence regarding this article
should be directed to: Rosa Maria M. 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, Brazil. Phone: +55 (51) 3308-5066. Fax:
+55 (51) 3308-5470. E-mail: rosa_almeida@yahoo.com or
rosa.almeida@ufrgs.br
Introduction
Impulsive aggression is a behavioral disposition
characterized by an inability to regulate affect and the
impulse to harm oneself or others (Lesch, Araragi,
Waider, van den Hove, & Gutknecht, 2012), and it is
highly comorbid with depression, substance use, and
suicidal behaviors (Seo, Patrick, & Kennealy, 2008).
In animal models, violence is dened as a form of
escalated aggressive behavior that is related to a lack
of control (de Almeida, Ferrari, Parmigiani, & Miczek,
2005; Miczek, de Almeida, Kravitz, Rissman, de Boer,
& Raine, 2007; Miczek, Fish, De Bold, & De Almeida,
2002). This behavior may be predisposed by serotonin
(5-hydroxytryptamine [5-HT]) deciency in emotion
regulation circuitry (New et al., 2002), in addition
to the contribution of dopamine hyperfunction to
serotonin deciency (Seo et al., 2008). Furthermore,
the dysfunctional relationship between serotoninergic
and dopaminergic neurons in the prefrontal cortex may
be an important mechanism that connects impulsive
aggression to comorbid disorders.
To control aggressiveness, a person’s diet may be
an important factor. Such behavior can be modulated
by supplementation with low doses of tryptophan (Trp).
Diets rich in Trp can modulate behavior in various
species, including sh (matrinxã Brycon amazonicus;
Wolkers, Serra, Hoshiba, & Urbinati, 2012), sows
(Li, Baidoo, Johnston, & Anderson, 2011), dogs
(Bosch, Beerda, Hendriks, van der Poel, & Verstegen,
2007), horses (Grimmett, & Sillence, 2005), Wistar
rats (Kantak, Hegstrand, Whitman, & Eichelman,
1980), and mice (Kantak, Hegstrand, & Eichelman,
1980). Tryptophan deciency might also lead to
an intensication of aggression in several species,
including humans (Miczek et al., 2002). This essential
amino acid is transported into the brain by a transporter
located in the blood-brain barrier (BBB) and acts as a
precursor for 5-HT synthesis in neurons. The synthesis
of serotonin in the brain is assumed to be proportional to
the quantity of Trp transported into the brain (Pardridge,
1998). The levels of this neurotransmitter are essential
for the inhibition of aggression (Nelson, & Chiavegatto,
2001) and can regulate emotion and behavior (Mann,
1995; Virkkunen, Goldman, Nielsen, & Linnoila, 1995).
Aggressive reactions toward intruders observed
in resident males are considered a natural response,

398 Walz et al.
representing a genetically dened adaptive reaction
that seeks to defend territory (Kulikov, & Popova,
1998; Olivier, & Young, 2002). Despite the fact that
diverse studies have reported a negative correlation
between aggression and 5-HT levels in studies that
used the resident-intruder paradigm, the results remain
contradictory. For example, Mosienko et al. (2012)
reported a correlation between enhanced aggression
and serotonin deciency in mice using this paradigm
(Mosienko et al., 2012). In contrast, using the same
model, Kulikov et al. (2012) reported an opposite
correlation between serotonergic activity and aggressive
behavior in mice (Kulikov, Osipova, Naumenko,
Terenina, Mormède, & Popova, 2012).
The present study evaluated whether acute oral Trp
administration decreases aggressive behavior in male
mice subjected to the resident-intruder paradigm.
Materials and Methods
Animals
We used 65 adult male and female CF1 strain
mice (Mus musculus), weighing 30-40 g. The animals
were provided by the State Foundation for Research
and Production in Health in Porto Alegre, Brazil, and
maintained in compliance with the National Institutes
of Health Guide for the Care and Use of Laboratory
Animals. All of the animals were kept in a room with
controlled temperature (23 ± 2ºC), 50-60% relative
humidity, and a 12 h/12 h light/dark cycle. They were
housed in polycarbonate cages (28 × 17 × 14 cm) that
were lined with pine shavings. The animals received
water and food (ration specic to rodents) ad libitum.
Resident-intruder paradigm
We used the resident-intruder paradigm to evaluate
offensive aggressive behavior. This test is based on
the fact that an adult male mouse will establish a
territory when given sufcient living space and will
attack unfamiliar males that intrude in its home cage
(Koolhaas, Coppens, de Boer, Buwalda, Meerlo, &
Timmermans, 2013). Male mice were divided into two
groups: residents (n = 65) and intruders (n = 80). The
animals in the intruder group were housed in groups
of 10. The animals in the resident group were housed
in individual cages accompanied by a female mouse
because territoriality is strongly enhanced in the presence
of females or sexual experience (Albert, Dyson, Walsh,
& Petrovic, 1988). After a 21-day period of adaptation,
each resident mouse was subjected to successive
confrontations with an intruder male three times per
week, with a minimum interval of 48 h, with the purpose
of establishing baseline aggressive behavior. During the
test, the female and pups were removed when the male
intruder was introduced into the cage. This test lasted 5
min and was recorded with a video camera. Behavior
was later analyzed with a computer software program
to analyze the previously constructed behaviors. The
behavioral repertoire, previously dened by Miczek, &
O’Donnell (1978), included the frequency of aggressive
elements, such as snifng the intruder, lateral attacks,
biting, pursuit, and tail rattling, and the duration of non-
aggressive behavior.
When the baseline was establish, the animals were
divided into ve groups (Vehicle and 10, 20, 30, and 100
mg/kg Trp; n = 13 per group).
Oral tryptophan administration
Each animal received a dose of Trp (10, 20, 30,
or 100 mg/kg) or vehicle by gavage 30 min before
each behavioral test. Tryptophan (Ajinomoto,
Japan) was diluted in a solution that contained 5%
carboxymethyl cellulose. The nal concentrations of
the Trp solution were 1%, 2%, 3%, and 10% in a nal
volume of 30 ml. Tryptophan was weighed with the
aid of a precision analytical balance and diluted with
a magnetic stirrer.
Behavioral test
Each resident was subjected to successive
confrontations with an intruder male. Each session
lasted 5 min, twice per week, with a minimum interval
of 72 h for at least 30 days. All of the sessions were
recorded for later analyses. The behaviors were analyzed
with the aid of computer software (Noldus, Observer,
Netherlands) by a trained observer. The frequencies,
durations, and temporal and sequential patterns of all
of the observed behavioral acts and postures in the
combatants during these confrontations were recorded,
providing a detailed quantitative assessment of offensive
(resident) aggression. Aggressive elements, including
frontal attack, side attack, biting the body and head of
the intruder, aggressive stance, domination, aggressive
cleaning, social investigation, walking, rearing, and
grooming, and the frequency and duration of non-
aggressive behaviors, including walking, self-cleaning,
and standing, were analyzed.
Statistical analysis
All of the data were homogeneously distributed and
are expressed as mean ± SEM. The effects of different
tryptophan concentrations were analyzed using a one-
way analysis of variance (ANOVA). Signicant effects
in the ANOVA (p < .05) were followed by Dunnett’s
post hoc test to compare the drug treatments with the
corresponding vehicle group. All of the statistical
analyses were performed using SPSS 18 software.
Results
Analysis of non-aggressive behavior
Non-aggressive behaviors, such as walking, rearing,
and grooming, were not statistically different compared
with the vehicle group (Table 1)
Analysis of aggressive behaviors
The results showed that the mean frequency of
aggressive behavior was signicantly different in the

Tryptophan and aggression 399
30
20
10
0
Frequency of Attack Bites
vehicle 10 mg/kg 20 mg/kg 30 mg/kg 100 mg/kg
Tryptophan Dosage
30
20
10
0
Frequency of Lateral Threats
vehicle 10 mg/kg 20 mg/kg 30 mg/kg 100 mg/kg
Tryptophan Dosage
Table 1. Duration (in seconds) of non-aggressive behaviors in male mice after receiving different concentrations of tryptophan.
Frequency Vehicle
(n = 13)
Tryptophan
10 mg/kg
(n = 13)
Tryptophan 20 mg/kg
(n = 13)
Tryptophan
30 mg/kg (n = 13)
Tryptophan
100 mg/kg (n = 13)
Walking 72.36 ± 12.91 60.54 ± 11.46 65.92 ± 16.70 62.13 ± 15.44 61.28 ± 13.35
Grooming 19.13 ± 6.06 21.51 ± 6.63 15.44 ± 3.71 17.28 ± 7.09 13.64 ± 3.93
Sning the intruder 6.46 ± 2.25 7.38 ± 1.91 8.10 ± 2.66 7.28 ± 2.04 8.03 ± 1.91
Rearing 39.85 ± 8.77 43.69 ± 7.33 43.90 ± 7.30 44.85 ± 6.53 47.95 ± 7.21
Figure 2. Frequency of lateral threats in male mice against
a male intruder after receiving different concentrations of
tryptophan.
Table 2. Frequency of aggressive behaviors in male mice against a male intruder after receiving different concentrations of
tryptophan.
Frequency Vehicle
(n = 13)
Tryptophan 10 mg/
kg
(n = 13)
Tryptophan
20 mg/kg
(n = 13)
Tryptophan 30
mg/kg
(n = 13)
Tryptophan 100
mg/kg
(n = 13)
Tail rattle 19.10 ± 2.26 17.87 ± 3.05 18.51 ± 3.66 17.15 ± 2.83 15.97 ± 2.61
Pursuit .10 ± .10 .10 ± .10 .28 ± .20 .12 ± .12 .17 ± .14
Figure 1. Frequency of attack bites (ghting) in male mice
against a male intruder after receiving different concentrations
of tryptophan.

400 Walz et al.
animals treated with 10 and 20 mg/kg Trp compared
with the control (vehicle) group. The number of attacks
(F4,52 = 12.27, p = .04) decreased compared with
the vehicle group (Figure 1), with a decrease in the
number of lateral threats (F4,52 = 31.10, p = .02; Figure
2). Other aggressive behaviors, such as tail rattling and
pursuit of the intruder, were not signicantly different
from the control group (Table 2).
Discussion
The present study tested 10, 20, 30, and 100 mg/kg
concentrations of Trp and analyzed aggression in male
mice in a territorial paradigm. We demonstrated that Trp
at concentrations of 10 and 20 mg/kg reduced aggressive
behavior in mice, specically the number of attack bites
and lateral threats. These results might indicate the
involvement of 5-HT in aggression, mainly because Trp
is the precursor for 5-HT in the brain. Importantly, non-
aggressive behaviors, such as walking, grooming, and
rearing, were not altered by Trp treatment at any of the
concentrations, conrming that the differences were not
attributable to alterations in locomotor activity.
Manipulating dietary L-tryptophan and consequently
5-HT levels to decrease aggressive behavior is not
a recent notion (Kantak et al., 1980; Kantak et al.,
1980; Valzelli, 1973; van Hierden, de Boer, Koolhaas,
& Korte, 2004). The rst indication that 5-HT can
inhibit aggressive behavior came from studies in which
neurotoxic agents, such as para-chlorophenylalanine
and 5,7-dihydroxytryptamine, decreased the levels of
this neurotransmitter. An inverse relationship between
5-HT levels and aggression has been found in both
animals and humans (Bjork, Dougherty, Moeller,
Cherek, & Swann, 1999). Most of the results in humans
were based on measurements of the main metabolite
of serotonin, 5-hydoxyindoleacetic acid (5-HIAA),
in cerebrospinal uid. In animals models, 5-HT and
5-HIAA can be measured directly in the brain, and the
inverse relationship between functional serotonergic
activity and aggression can be easily established.
However, several contradictory results have been found,
and one study found a positive relationship between
5-HT and aggression (Kulikov et al., 2012).
Notably, no differences were found at the higher
doses of Trp (30 and 100 mg/kg). In mice that
received 30 or 100 mg/kg Trp, the high serotonin
levels may have promoted negative feedback through
serotoninergic autoreceptors (5-HT1A and 5-HT1B), thus
diminishing the release of serotonin and consequently
enhancing aggressiveness. The overstimulation of
presynaptic autoreceptors might lead to autoinhibition
of the serotoninergic system through a feedback
mechanism (Popova, 2006). Nonetheless, more studies
are necessary to clarify this hypothesis. The respective
roles of 5-HT1A and 5-HT1B receptors in modulating
aggressive behavior remain a source of debate (De
Almeida, & Lucion, 1997; Millan et al., 1997; Mos,
Olivier, Poth, Van Oorschot, & Van Aken, 1993;
Sanchez, & Hyttel, 1994; Sijbesma, Schipper, de Kloet,
Mos, van Aken, & Olivier, 1991). Consistent with
the present results, evidence indicates that the anti-
aggressive effects of 5-HT1A receptor stimulation are
caused by activation of postsynaptic 5-HT receptors
(Sijbesma et al., 1991; Mos, Olivier, Poth, & van Aken,
1992; Mos et al., 1993; Olivier, & van Oorschot, 2005).
Studies with 5-HT1B full and partial receptor agonists,
such as CP-94,253, eltoprazine, TFMPP, zolmitriptan,
and anpirtoline, have consistently reported anti-
aggressive effects, regardless of the basal levels of
aggressive behavior (de Almeida, & Miczek, 2002;
Miczek et al., 2002; Mos et al., 1992; Olivier, & Mos,
1986), which may be mediated by somatodendritic
autoreceptors (Bannai, Fish, Faccidomo, & Miczek,
2007) or postsynaptic heteroreceptors (de Almeida,
Faccidomo, Fish, & Miczek, 2001).
Several studies have shown that actions on 5-HT1A
and 5-HT1B receptors modulate aggressive behavior, but
we believe that 5-HT1B receptors play a primary role in
inhibiting aggression. The study by da Veiga, Miczek,
Lucion, & de Almeida (2011) demonstrated a decrease
in maternal aggressive behavior after concomitant
microinjections of 5-HT1B receptor agonists into the
ventral orbital prefrontal cortex and dorsal raphe nucleus
in female postpartum rats that were socially instigated,
and the activation of these receptors modulated high
levels of aggression in a behaviorally specic manner,
possibly because of the activation of 5-HT1B receptors at
the soma and terminals.
In conclusion, the present ndings indicate
that low doses of Trp are able to reduce aggressive
behavior in male mice in the resident-intruder
paradigm. Tryptophan supplementation may be an
alternative treatment for aggression in groups that
exhibit such behavior. Further studies should test this
diet for different periods of time and verify the effects
on aggression in different species.
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