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679
Does Serotonin Influence Aggression? Comparing Regional Activity
before and during Social Interaction*
Cliff H. Summers
1,†
Wayne J. Korzan
1
Jodi L. Lukkes
1
Michael J. Watt
1
Gina L. Forster
1
Øyvind Øverli
1,2,‡
Erik Ho¨glund
1,2
Earl T. Larson
3
Patrick J. Ronan
1,4
John M. Matter
5
Tangi R. Summers
1
Kenneth J. Renner
1
Neil Greenberg
6
1
Biology and Neuroscience, University of South Dakota,
Vermillion, South Dakota 57069;
2
Division of General
Physiology, Department of Biology, University of Oslo, P. O.
Box 1051 Blindern, N-0316 Oslo, Norway;
3
Departments of
Biology and Psychology, 134 Mugar Hall, Northeastern
University, Boston, Massachusetts 02115;
4
Avera Research
Institute and Veterans Administration Research Service,
Royal C. Johnson Medical Center, 2501 West 22nd Street,
Sioux Falls, South Dakota 57105;
5
Department of Biology,
Juniata College, Huntingdon, Pennsylvania 16652;
6
Department of Ecology and Evolutionary Biology, University
of Tennessee, Knoxville, Tennessee 37996
Accepted 11/4/2004; Electronically Published 7/29/2005
ABSTRACT
Serotonin is widely believed to exert inhibitory control over
aggressive behavior and intent. In addition, a number of studies
of fish, reptiles, and mammals, including the lizard Anolis car-
olinensis, have demonstrated that serotonergic activity is stim-
ulated by aggressive social interaction in both dominant and
* This article is based on a presentation given in the symposium “Integration
of Behaviour and Physiology,” which took place at the Society for Experimental
Biology annual meeting, Heriot-Watt University, Edinburgh, Scotland, March
29–April 2, 2004.
†
Corresponding author; e-mail: cliff@usd.edu.
‡
Present address: Department of Animal and Aquacultural Sciences, Norwegian
University of Life Sciences, P. O. Box 5003, N-1432 Aas, Norway.
Physiological and Biochemical Zoology 78(5):679–694. 2005. 䉷 2005 by The
University of Chicago. All rights reserved. 1522-2152/2005/7805-4061$15.00
subordinate males. As serotonergic activity does not appear to
inhibit agonistic behavior during combative social interaction,
we investigated the possibility that the negative correlation be-
tween serotonergic activity and aggression exists before ag-
gressive behavior begins. To do this, putatively dominant and
more aggressive males were determined by their speed over-
coming stress (latency to feeding after capture) and their celerity
to court females. Serotonergic activities before aggression are
differentiated by social rank in a region-specific manner.
Among aggressive males baseline serotonergic activity is lower
in the septum, nucleus accumbens, striatum, medial amygdala,
anterior hypothalamus, raphe, and locus ceruleus but not in
the hippocampus, lateral amygdala, preoptic area, substantia
nigra, or ventral tegmental area. However, in regions such as
the nucleus accumbens, where low serotonergic activity may
help promote aggression, agonistic behavior also stimulates the
greatest rise in serotonergic activity among the most aggressive
males, most likely as a result of the stress associated with social
interaction.
Introduction
Studies in fish (Winberg et al. 2001; Perreault et al. 2003),
reptiles (Deckel 1996; Deckel and Jevitts 1997; Deckel and Fu-
qua 1998; Larson and Summers 2001), birds (Fachinelli et al.
1989; Ison et al. 1996; Sperry et al. 2003), mammals (Ferris et
al. 1997), primates (Raleigh et al. 1991), and humans (Berggard
et al. 2003; Lai et al. 2003; Reist et al. 2003) suggest that se-
rotonin (5-HT) is the primary inhibitory regulator of aggressive
behavior. However, it is becoming clear that aggressive behavior
is regulated by more systems, probably including 5-HT, do-
pamine, GABA, and glutamate (Miczek et al. 2002; Baxter
2003). A number of excellent studies have demonstrated roles
for vasopressin (Ferris and Delville 1994; Delville et al. 1996;
Ferris 1996, 2000; Ferris et al. 1997; Coccaro et al. 1998), nitric
oxide (Nelson and Chiavegatto 2000; Chiavegatto et al. 2001;
Chiavegatto and Nelson 2003), anabolic steroids (Melloni and
Ferris 1996; Melloni et al. 1997), and corticosterone (Kruk
1991, 2002; de Kloet et al. 1996; Siegel et al. 1999; Haller et al.
2000a, 2000b, 2001; Hala´sz et al. 2002a), but most suggest that
inhibitory regulation of aggression is 5-HT dependent. In fact,
Nelson and Chiavegatto recently opined that 5-HT remains the
primary molecular determinant of intermale aggression; despite
the fact that many other molecules appear involved, they do
680 C. H. Summers et al.
so indirectly through 5-HT signaling (Nelson and Chiavegatto
2001).
The regions comprising the primary neural circuitry for ag-
gression and additional regions that modify aggression probably
include the medial amygdala, prefrontal cortex, hippocampus,
septum, bed nucleus of the stria terminalis, mediodorsal tha-
lamic nucleus, ventral tegmentum, and the periaqueductal gray
and hypothalamic “attack area” (Kruk 1991; Gregg and Siegel
2001; Hala´sz et al. 2002b) and are all rich in 5-HT
1A
and 5-
HT
1B
receptor subtypes (Simon et al. 1998). The pattern of
innervation of most of the brain by a small group (B
1
–B
12
)of
serotonergic neurons in the midbrain and pontine raphe and
reticular nuclei is conserved throughout vertebrates (Jacobs and
Azmitia 1992). A major theory on serotonergic function sug-
gests that the activities of this limited group of 5-HT-producing
cells and their very wide terminal distribution are tightly co-
ordinated, producing a rather uniform and pervasive release in
terminal regions, with the primary function of the brain sero-
tonergic system to facilitate arousal and motor output (Jacobs
and Fornal 1999).
However, the hypotheses that (1) the sole function of sero-
tonergic systems in the brain is to facilitate behavioral arousal
and motor activity (Jacobs and Fornal 1999) and that (2) 5-
HT is the primary molecular determinant of aggression (Nelson
and Chiavegatto 2001) are fundamentally incompatible. Sero-
tonergic activity cannot be inhibiting motor patterns of ag-
gression at the same time as it is stimulating motor activity,
especially if serotonergic activity is supposed to be uniform.
However, the raphe nuclei have been demonstrated to have
diverse morphological features and distinct topographical dis-
tributions (Steinbusch 1984; Valentino et al. 2001; Lowry 2002;
Kirby et al. 2003). Topographically organized subpopulations
within serotonergic nuclei have specific differential effects on
physiological and behavioral responses to stress and stress-
related neuromodulators (Lowry et al. 2000; Hammack et al.
2002; Summers et al. 2003a). It has been argued that although
stressors activate serotonergic systems, they do so no more than
other activating conditions (Jacobs and Fornal 1999). Unfor-
tunately, to argue this point is to misunderstand the very nature
of stress responsiveness and the role of the serotonergic systems
therein. As Selye and Cannon speculated early in the devel-
opment of this field, activating conditions, both positive (af-
firmative, optimistic, pleasurable) and negative (harmful, pes-
simistic, distressing), are stressors because they describe a
biological state of disrupted homeostasis via mechanisms sen-
sitive to nonspecific changes in external, psychological, and
social environments (Cannon and Paz 1911; Cannon 1914;
Selye 1936, 1937, 1975).
A variety of stressors induce elevated central serotonergic
activity, especially in limbic regions. As an example, restraint
stress has been demonstrated to stimulate serotonergic activity
and 5-HT receptor numbers in rats (Yau et al. 2001; Torres et
al. 2002; Yamato et al. 2002; Gamaro et al. 2003), lizards (Em-
erson et al. 2000), pigs (Piekarzewska et al. 2000), and primates
(Dinzburg et al. 1992). Social confrontations that include ag-
gressive intent, posturing, or actions are salient stressors for
both the aggressor and the target of aggression (Miczek et al.
2002). Therefore, social stress, which includes aggressive be-
haviors and social corollaries, also stimulates serotonergic ac-
tivity (Winberg and Nilsson 1993a; Summers 2001; Summers
et al. 2003b). The central circuitries that serve stress and ag-
gression overlap. The central and medial amygdala, nucleus
accumbens, and adjacent regions in the hypothalamus are in-
volved in both stress and aggression. Stress and aggression are
linked, via motivation and reward, such that frustration in the
absence of reward produces significant increase in synaptic ac-
tivity in the neural circuitry controlling aggression (David et
al. 2004). In addition, stress modifies the ontogenetic devel-
opment of aggressive behavior (Wommack et al. 2003; Delville
et al. 2003). Behaviorally, experiments that produce frustration
by removing reward provoke intense aggression (Gallup 1965;
Azrin et al. 1966; Cherek and Pickens 1970).
Although aggressive interactions are stressful for both dom-
inant and subordinate individuals (Øverli et al. 1999; Summers
2002; Miczek et al. 2002), the increase of serotonergic activity
attributable to stress is at odds with inhibited serotonergic func-
tion during aggression. How can 5-HT release and use rise as
a result of a stressful event like aggression, when elevated sero-
tonergic activity is supposed to inhibit aggression? In addition,
it is true that no simple one-to-one causal relationship has been
found between serotonergic activity and aggression in animals,
including humans (Krakowski 2003). As Miczek et al. (2002)
have pointed out, changed serotonergic parameters measured
after aggression do not establish a causal relationship between
decreased serotonergic activity and increased aggression. They
also have shown that although 5-HT release is evident in the
prefrontal cortex of aggressive male rats, it is detectable only
once a resident rat is already attacking an intruder (van Erp
and Miczek 2000). The probability of a causal relationship be-
tween 5-HT and aggression requires understanding local
changes in specific brain regions of serotonergic parameters
before, during, and after the aggressive interaction. It is also
important to recognize that effects of 5-HT on aggressive be-
havior are time, region, and context dependent and that the
relationship between 5-HT and aggression may be complex.
The purpose of the work described here was to measure sero-
tonergic activity, before aggression occurs, in animals known
to possess elevated aggressive predisposition and to compare it
with that in more docile conspecifics. We hypothesized as fol-
lows: (1) Serotonergic activity of aggressive male Anolis caro-
linensis lizards would be significantly lower than that of non-
aggressive animals in regions of the brain that are associated
with aggression. We suggest that those regions include the an-
terior hypothalamus, nucleus accumbens, medial amygdala,
septum, and raphe. (2) Serotonergic activity should not be
globally reduced in aggressive males. Regions not specifically
5-HT and Aggression 681
Figure 1. Percent of the average latency to feeding (top) and courtship
(bottom) of male Anolis carolinensis as predictors of aggressive behavior
(and sampled for this experiment; left), compared with a similar sample
of lizards that were tested for aggression (right). The zero point on
the graph is equivalent to the population mean. The most aggressive
males also fed and courted significantly sooner and became dominant
(white bars). Therefore, all males with a shorter latency to feeding or
courtship were presumed to be aggressive and dominant. Less ag-
gressive males became subordinate (black bars) and had longer latencies
to feeding and courtship. All males that recovered more slowly from
the stress of caging and postponed eating and showed delayed courtship
toward a novel female were presumed to be less aggressive and
subordinate.
associated with aggression neurocircuitry, such as the hippo-
campus or lateral amygdala, should not exhibit differences in
basal serotonergic activity in aggressive versus nonaggressive
lizards. (3) The largest increases in serotonergic activity during
aggression occur in the most aggressive males, especially in
regions such as the nucleus accumbens, in which aggression
and stress-related neurocircuitries overlap.
Material and Methods
Animals
Adult male (
160-mm snout-vent length) Anolis carolinensis were
obtained from a commercial supplier (Marabella’s, Gonzales,
LA). Each animal was weighed, had its snout-vent length mea-
sured, and was housed individually in a (25 cm)
3
terrarium with
a wooden perch (Korzan et al. 2000a). Room lights (14L : 10D),
temperature (32⬚C in light, 20⬚C in darkness), and relative hu-
midity (70%–80%) were regulated to maintain gonadal activity
(Licht 1971). All animal experiments were carried out in ac-
cordance with the National Institutes of Health Guide for the
Care and Use of Laboratory Animals (NIH Publication 80-23),
under protocol approved by the University of South Dakota
Institutional Animal Care and Use Committee. In addition, all
efforts were made to minimize the number of animals used
and their suffering. After arrival, lizards were given water ad
lib. Each cage held two lizards, separated by an opaque divider.
There were no significant differences in mean initial weights
or snout-vent lengths between pairs or treatment groups.
Determination of Aggressiveness and Social Status
To determine the capacity for aggressive reaction before combat,
36 male A. carolinensis lizards were tested for readiness to feed
and latency to court females (Korzan et al. 2004). After arrival
from a commercial supplier, the animals were placed individ-
ually in cages and presented one cricket each day. If the cricket
was eaten, it was recorded for that day; if not, it was removed
after 5 min. The latency to feeding, in days, for each lizard was
recorded (Fig. 1, top). After a week of acclimation to the cage
plus a week of consistent feeding by all males, each male was
presented with a sexually active female. Female reproductive
status is discernible by palpation of the abdomen (Summers et
al. 1985). The latency to courtship display by the resident male
was measured and recorded (Fig. 1, bottom). Courtship displays
of male A. carolinensis are distinguishable from aggressive dis-
plays by the speed of the head nod during courtship (Crews
1975). Head nods during courtship displays are comprised of
rapid shuddering (DeCourcy and Jenssen 1994). Males inter-
acting to a size-matched opponent that had previously fed
within the first day after being caged and those that vigorously
courted a female within 60 s were faster to produce aggressive
display and were more aggressive than 82% of all other males
( dominant and 15 subordinate aggression-testedN p 15
males). Males having a shorter latency to courtship displays
toward females become dominant 89% of the time (Korzan et
al. 2004). Those with a shorter latency to feeding become dom-
inant 79% of the time. These males could be counted on to
attack an opponent in less than 200 s and behave aggressively
more than 40 times in the first 10 min.
682 C. H. Summers et al.
Preparation and Treatment of Brain Tissue
Heads were rapidly removed while on a dry ice/ice mixture
within 15 s of capture and then frozen at ⫺80⬚C. Brains, still
in the braincase, were cut frozen (IEC cryostat at ⫺13⬚C) into
serial 300-mm sections, thaw-mounted on glass slides, and then
refrozen for microdissection. Brain regions were identified us-
ing a stereotaxic atlas of the A. carolinensis brain (Greenberg
1982) and a map of central catecholamines (Lopez et al. 1992)
and then microdissected with a 300-mm-diameter cannula
(Summers et al. 2003b). Regions chosen for analysis included
the CA
3
region of the hippocampus (dorsomedial cortex is
approximately equivalent to Ammon’s horn; ), the sep-N p 7
tum ( ), the nucleus accumbens ( ), the striatumN p 7 N p 14
( ), the lateral amygdala ( ), the medial amygdalaN p 6 N p 7
( ), the anterior hypothalamus ( ), the posteriorN p 16 N p 6
hypothalamus ( ), the raphe ( ), the locus ceru-N p 17 N p 17
leus ( ), the substantia nigra ( ), and the ventralN p 16 N p 6
tegmental area ( ). Variable sample size follows from dataN p 18
collection of controls from three concurrent experiments in
various stages of high-performance liquid chromatography
(HPLC) analyses but with experimental design and HPLC pa-
rameters remaining consistent for all experiments. These
regions were chosen on the basis of regions known to be as-
sociated with aggression neural circuitry (Kruk 1991; Delville
et al. 2000; Gregg and Siegel 2001; Hala´sz et al. 2002b)inother
species and of homologies to mammalian systems (Bruce and
Neary 1995a, 1995b, 1995c).
Analysis of Monoamines by HPLC
Serotonin (5-HT) and its metabolite 5-HIAA (5-hydroxyin-
doleacetic acid) were measured using HPLC with electrochem-
ical detection (Emerson et al. 2000). The data are presented as
ratios of catabolite to transmitter (i.e., ), which5-HIAA/5-HT
is an estimate of monoaminergic turnover and activity. Mono-
aminergic activity is often approximated by the ratio of the
catabolite to transmitter and is especially important for ana-
lyzing serotonergic activity in studies of behavior or stress
(Summers 2001). Accessible 5-HT is often greater than demand
for individual or even multiple behavioral events; hence, 5-HT
levels often remain unchanged. Constant 5-HT levels may also
occur when synthesis is rapidly elevated in response to stress,
because production may offset release. Behavior- or stress-
induced changes in the catabolite 5-HIAA are often seen along
with changes in (Winberg and Nilsson 1993a).5-HIAA/5-HT
However, the ratio is a more direct index of serotonergic activity
than catabolite levels per se, because variance related to tissue
sampling and to total levels of 5-HT and 5-HIAA is reduced
(Shannon et al. 1986). Although changes in ratio are often a
result of changes in 5-HIAA levels, experiments that imme-
diately follow behavioral interaction may discern a reduction
in 5-HT concentrations reflecting recent release and having a
greater effect than 5-HIAA levels on the ratio.
Punched brain samples were expelled into 60 mL of a sodium
acetate buffer (pH 5) containing a-methyl dopamine (internal
standard), freeze-thawed, and centrifuged at 15,000 g for 2 min.
The supernatant was removed, and 45 mL was injected into a
chromatographic system (Waters Associates) and analyzed elec-
trochemically with an LC-4B potentiostat (Bioanalytical Sys-
tems). The electrode potential was set at ⫹0.6 V with respect
to an Ag/AgCl reference electrode. The output was recorded
by CSW 32 version 1.4 Chromatography Station (Data Apex,
Prague).
Comparison of 5-HIAA/5-HT before and “during” Aggression
To analyze the prospective responsiveness of the serotonergic
system in potentially aggressive (total ) and unaggressiveN p 18
(total ) animals, we compared the values taken fromN p 18
this experiment with those measured previously in males
( dominant and 9 subordinate males) behaving aggres-N p 9
sively at 10 min (Summers et al. 2003b). The previous exper-
iment had been implemented in the same general fashion as
the experiments reported here, with pretesting of males for
receptiveness to females and food. However, in the previous
experiment, males were allowed to fight, and dominant-
subordinate relationships were formed. Brains were removed
and monoamines measured as described above. The 10-min
time point was chosen because it is has been the focal point
of numerous other studies and because at that time the ag-
gressive interaction is ongoing but close to the end (Summers
2002). At that point, dominant and subordinate social roles
have been established, and the more aggressive combatant is
clearly indicated. The areas analyzed for this comparison are
limited to those available from the previous study. To determine
the change in serotonergic activity from before to “during” the
fight, we first made each value for putatively5-HIAA/5-HT
aggressive (those with short feeding and courtship latencies)
and unaggressive males (those with longer feeding and court-
ship latencies) a percentage of the population mean (i.e., the
mean for all aggressive and unaggressive individuals sampled,
, presented in Fig. 2). Then, for both the dominantN p 36
aggressive and subordinate less aggressive males, the mean
levels measured at 10 min were calculated as a5-HIAA/5-HT
percent of control (i.e., isolated males) values from Summers
et al.’s (2003b) experiment. Finally, the percent value for each
animal before aggression (Fig. 2) was subtracted from the mean
percent value during aggression.
Corticosterone Analyses
Plasma corticosterone (B in figures) concentrations ( )N p 12
were measured by direct enzyme-linked immunoabsorbent assay
(Octeia, IDS) from blood collected after decapitation. Plasma (30
5-HT and Aggression 683
Figure 2. Percent difference in serotonergic activity (estimated by the
ratio of 5-hydroxyindoleacetic acid to 5-hydroxytryptamine [seroto-
nin]: ) between males predetermined to be ag-5-HIAA/5-HT Ⳳ SEM
gressive and dominant (white bars) and those less aggressive and sub-
ordinate (black bars) before any aggressive interaction. The zero point
on the graph is equivalent to the population mean. Determination of
aggressive status was accomplished by two tests, one for latency to
feeding and the other for latency to courtship. Males that recover from
the stress of caging fastest, and therefore eat sooner, and males that
court a novel female more quickly become dominant. Hippo CA3 p
3 of the cornu ammonis of the hippocampus,region NAccp
accumbens, amygdala,nucleus lAmyg p lateral mAmyg p medial
amygdala, area, hypothalamus,POA p preoptic AH p anterior
hypothalamus, nucleus,LH p lateral PVN p paraventricular
hypothalamus, ceruleus,VMH p ventromedial LC p locus SN p
nigra, tegmental area; .substantia VTA p ventral B p corticosterone
mL) was added to 270 mL of diluent, of which 100 mL was added
to an assay plate, as were standard curve samples. To all wells of
the assay plate was added 100 mL of corticosterone-horseradish
peroxidase conjugate. The plate was incubated at 4⬚C for 24 h
and washed (Bio-Tek Elx50), and 200 mL of TMB substrate was
added to each well. The samples and standard curve were in-
cubated at 25⬚C for 30 min, and 100 mL of stop solution was
added. Corticosterone levels were determined by reading the
absorbance of samples at 450 nm (Bio-Tek EL800) and calcu-
lating the concentration from the standard curve.
Results
Aggressive Potential
The animals used in these experiments were tested for latency
to feeding and courtship and compared with animals previously
tested for the same parameters and subsequently tested for
aggressiveness and social rank (Fig. 1). As with aggression-tested
males, there were males among the sampled population that
were significantly faster or significantly slower than average to
feed or court. For our experiment, putatively dominant males
fed significantly sooner ( , ) than average andt p 2.03 P
! 0.048
were very similar in latency to feeding ( , ) tot p 0.34 P
1 0.73
dominant aggression-tested males. The distinction between
courtship latency for putatively dominant and subordinate
males was significantly more robust ( , ) fort p 4.92 P
! 0.00001
the currently reported samples (Fig. 1, bottom left) than for
those animals that were aggression tested ( , ).t p 2.13 P
! 0.042
For this experiment, we were particularly conservative in choos-
ing putatively subordinate unaggressive males, and they were
significantly slower ( , ) to court females thant p 3.34 P
! 0.003
were subordinate aggression-tested males (Korzan et al. 2004),
although in both cases, unaggressive subordinate males were
significantly slower than dominant aggressive males. However,
dominant males had virtually identical ( , ) la-t p 0.01 P
1 0.99
tencies to court whether they were aggression tested or not
(Fig. 1, white bars).
Serotonergic Activity Based on Aggressive Potential
Using the ratio as an estimate of serotonergic5-HIAA/5-HT
turnover and activity, we found that males prejudged to be
aggressive by feeding and courtship tests (Fig. 1) exhibited sig-
684 C. H. Summers et al.
Figure 3. Percent change in serotonergic activity (ⳲSEM), estimated
by comparing males predetermined to be aggressive and dominant
(white bars) or less aggressive and subordinate (black bars) before any
aggressive interaction with similarly appraised males after aggression.
The zero point on the graph is equivalent to the population control
mean. Determination of aggressive status before aggression was ac-
complished by two tests, one for latency to feeding and the other for
latency to courtship. The percent change in serotonergic responsiveness
was calculated by subtracting the percent (of control values) of
before aggression from the percent of5-HIAA/5-HT 5-HIAA/5-HT
measured during aggression. accumbens, mAmyg pNAccp nucleus
medial amygdala, ceruleus, .LC p locus B p corticosterone
nificantly lower serotonergic activity than nonaggressive males,
but only in specific brain regions. There was no globally ap-
parent effect of aggressiveness reducing brain serotonergicfunc-
tion, even though in the 5-HT–producing nuclei of the raphe,
aggressive males had significantly ( , ) lowert p 3.9 P
! 0.001
than nonaggressive males (Fig. 2, bottom). The5-HIAA/5-HT
locus ceruleus is a noradrenergic nucleus, and it also showed
significantly lower ( , ) serotonergic activity int p 2.7 P
! 0.019
lizards prejudged to be aggressive than in nonaggressive males.
The dopaminergic nuclei, substantia nigra, and ventral teg-
mental area, however, were not significantly different in sero-
tonergic activity in a comparison of aggressive and nonaggres-
sive male anoles.
In the forebrain, there were statistically lower
ratios in the septum ( , ), nu-5-HIAA/5-HT t p 3.7 P
! 0.001
cleus accumbens ( , ), striatum ( ,t p 3.3 P
! 0.007 t p 3.0 P !
), medial amygdala ( , ), and anterior hy-0.039 t p 2.69 P ! 0.02
pothalamus ( , ) among males that were quickert p 2.5 P
! 0.029
to feed and court and therefore also more likely to respond
sooner and with more aggression (Fig. 2, top and middle). On
the other hand, there was no significant difference in seroto-
nergic activity between aggressive and nonaggressive males in
the CA
3
region of the hippocampus, preoptic area of the hy-
pothalamus, or lateral amygdala.
Comparing Serotonergic Activity before and during Aggression
The relative change in in animals tested for5-HIAA/5-HT
aggressive capacity (but lacking actual agonistic interaction)
compared with males that actually did fight for social rank
revealed a significantly greater rise in serotonergic activity in
the nucleus accumbens ( , ) among aggressivet p 3.26 P
! 0.0076
dominant males (Fig. 3). In the raphe, there was a significantly
greater decrease in serotonergic activity ( , )t p 3.47 P
! 0.004
among less aggressive subordinate males. In the medial amyg-
dala ( , ) and locus ceruleus ( , ),t p 0.61 P
1 0.55 t p 1.4 P 1 0.18
although each region showed lower preagonistic serotonergic
activity in aggressive males, there was no difference in the in-
crease in once aggressive interaction had begun.5-HIAA/5-HT
Corticosterone
Plasma concentrations of corticosterone were also significantly
different ( , ) between males that were likely tot p 3.5 P
! 0.01
be aggressive and those likely to be nonaggressive based on
feeding and courtship latencies. Unlike serotonergic activity,
however, plasma corticosterone was elevated in potentially ag-
gressive males, compared with that in nonaggressive anoles (Fig.
2, bottom). The relative increase in plasma corticosterone con-
centrations was not significant ( , ) when com-t p 1.7 P
1 0.12
paring dominant aggressive males to less aggressive subordinate
males before and during a fight (Fig. 3).
Discussion
There is a large body of evidence to correlate lower 5-HT, or
serotonergic, activity with increased aggression and risky be-
havior (Nelson and Chiavegatto 2001; Miczek et al. 2002).
However, 5-HT systems are assembled from a very small num-
ber of cells in the midbrain and brain stem (Jacobs and Azmitia
1992) with diffuse and extremely divergent projection patterns
(Azmitia and Segal 1978). In addition, 5-HT is involved in a
large number of physiological and psychological events, such
as temperature regulation, sleep, locomotion, learning and
memory, sexual function, endocrine regulation, immune activ-
ity, and stress-related pathological syndromes such as post-
traumatic stress disorder, anxiety, and depression (Dinan 1996;
Geyer 1996; Graeff et al. 1996; Hidalgo and Davidson 2000;
Nutt 2000). Therefore, how could 5-HT possibly specifically
inhibit aggression? Our results indicate that reduced seroto-
nergic activity in specific regions of the brain occurs in more
aggressive Anolis carolinensis lizards (Fig. 2). Those results sug-
gest two things: (1) 5-HT may be causally related with ag-
gression, and (2) the effect is not global. Previous approaches
often suggested a relationship between global 5-HT function
and reduced aggression, as has been demonstrated by phar-
macological agents that influence serotonergic mechanisms
(Czlonkowski et al. 1975; Gibbons et al. 1979; Coccaro 1989;
Deckel 1996; Cleare and Bond 1997; Sperry et al. 2003).
5-HT and Aggression 685
Serotonergic Drugs
Serotonin reuptake inhibitors and neurotoxins. The chronic ap-
plication of selective serotonin reuptake inhibitors (SSRIs), in-
cluding fluoxetine (Prozac), sertraline (Zoloft), citalopram
(Celexa), paroxetine (Paxil), femoxetine, and fluvoxamine (Lu-
vox), is widespread in therapeutic treatment of affective dis-
orders, such as depression, bipolar disorder, and obsessive-
compulsive disorder, and to help curb addictions, such as
smoking. Chronic SSRI treatments have also been used to in-
hibit aggression in humans (Coccaro et al. 1997; Coccaro and
Kavoussi 1997) and even their pets (Dodman et al. 1996). Very
few studies, with the exception of that by Perreault et al. (2003),
have looked at the effects of both acute and chronic SSRI treat-
ment. Chronic treatment with SSRIs invariably depresses ag-
gressive behavior, and it does so in fish (Perreault et al. 2003),
reptiles (Deckel 1996; Deckel and Jevitts 1997; Larson and Sum-
mers 2001), birds (Hine et al. 1975; Sperry et al. 2003), and
mammals (Sa´nchez and Hyttel 1994; Delville et al. 1996; Vil-
lalba et al. 1997; DeLeon et al. 2002). Longer chronic treatment
with antidepressants, however, can increase aggressive behavior
in rodents, most likely reflecting increased assertiveness(Mitch-
ell and Redfern 2005). The serotonin neurotoxin 5,7-
dihydroxtryptamine promotes aggressive behavior and limits
submissive responses in rats (Ellison 1976; Vergnes et al. 1988;
Chung et al. 1999) and subordinate pigeons (Ison et al. 1996).
Acute SSRI treatment is rare but also appears to diminish
aggressive behavior. Perreault et al. (2003) demonstrated that
acute fluoxetine treatment of coral reef fish reduced aggressive
contact frequency and duration in Caribbean coral reef terri-
tories much as it had when given chronically in the lab. Similar
field studies demonstrated that acute fluoxetine reduced ag-
gression in birds (Sperry et al. 2003).
5-HT receptor drugs. The 5-HT
1A
agonists, including 8OH-
DPAT (which also has significant 5-HT
7
activity), buspirone,
and gepirone, or antagonists, such as WAY 100635, have been
demonstrated to inhibit or promote, respectively, aggression in
Anolis (Deckel and Fuqua 1998), sparrows (Sperry et al. 2003),
hamsters (Ferris et al. 1999), mice (Bell and Hobson 1994;
Miczek et al. 1998; Cologer-Clifford et al. 1999), and rats (Al-
bonetti et al. 1996; de Boer et al. 2000; Pruus et al. 2000).
Decreased 5-HT
1A
binding has also been demonstrated in more
aggressive humans (Parsey et al. 2002). Among the more con-
vincing experiments have been those in which 5-HT, 5-HT
1A
or 5-HT
1B
drugs, or SSRIs were locally injected into the hy-
pothalamus to inhibit aggressive behavior of hamsters (Ferris
and Delville 1994; Delville et al. 1996; Ferris 1996; Ferris et al.
1997, 1999). While the neuroactive peptide arginine vasopressin
facilitated aggression in hamsters, localized hypothalamic sero-
tonergic activity was enough to inhibit this behavior. These
data suggest, as do ours, that the influence of 5-HT on ag-
gression is a region-specific event. Other serotonergic receptors,
such as 5-HT
1B
, 5-HT
2A
, and 5-HT
3
, have also been implicated
in modulating aggressive behavior (Saudou et al. 1994; Rud-
issaar et al. 1999; Shih et al. 1999; Chiavegatto et al. 2001;
Miczek et al. 2002).
In studies of A. carolinensis, 5-HT
1A/7
, 5-HT
2
, and 5-HT
3
agonists (Deckel and Fuqua 1998), as well as the SSRIs fluox-
etine (Deckel 1996; Deckel and Jevitts 1997) and sertraline
(Larson and Summers 2001), all inhibit aggression. Although
these drugs are given peripherally and presumably have a global
effect enhancing serotonergic activity, our data suggest that the
effect of reducing aggression may be localized to specific brain
regions associated with aggression circuitry.
Evolutionary Conservation across Taxa
The organization of brain 5-HT systems appears to be re-
markably constant across vertebrate classes (Parent 1981; Jacobs
and Azmitia 1992). Serotonin-producing neurons project to
several behaviorally important areas, such as the hypothalamus,
hippocampus, amygdala, and prefrontal cortex (Azmitia and
Segal 1978).
Even among invertebrates, as in most animal species, sero-
tonin has been suggested to serve important roles in aggression
(Edwards and Kravitz 1997; Kravitz and Huber 2003). For ex-
ample, acute injection of 5-HT into the hemolymph of sub-
ordinate crayfish engendered a renewed willingness in these
animals to engage dominants in further agonistic encounters,
decreasing the likelihood of retreat (Huber et al. 1997). We
agree with an impression expressed in a recent review of ag-
gression in crayfish that although serotonergic systems have a
substantial involvement in aggression, they also appear to in-
fluence a spectrum of behaviors, and connecting 5-HT function
with motivational aspects of behavior remains elusive (Pank-
sepp et al. 2003).
A series of enlightening experiments in fish revealed a re-
lationship between serotonergic activity and socially stressful
aggressive interactions and suggested the possibility that the
inverse relationship between 5-HT and aggression was not so
simple (Winberg et al. 1992, 1996, 1997b, 2001; Winberg and
Nilsson 1993b; Øverli et al. 1999, 2001, 2004a; Elofsson et al.
2000; Lepage et al. 2000; Ho¨glund et al. 2001). Changes in 5-
HT systems even appear to underlie the aggressive behavioral
changes that develop accompanying sex change in coral reef
fish (Larson et al. 2003a, 2003b). All of these studies suggested
an increase in serotonergic activity during or after aggressive
interaction (Winberg and Nilsson 1993a). However, increased
serotonergic activity following tryptophan or SSRI treatment
can reduce territorial aggression in salmonids (Winberg et al.
2001) and coral reef fish (Perreault et al. 2003), and injection
of 5-HT itself can inhibit aggressive signals in electric fish
(Maler and Ellis 1987). Although these treatments that more
globally increase 5-HT will inhibit aggression, the effect of 5-
HT appears to be regionally specific in fish. Social defeat led
to increased 5-HT activity in both the amygdala and the hip-
686 C. H. Summers et al.
pocampus, while 5-HT systems appeared unaffected by social
interaction in trout paired repeatedly with a subordinate in-
dividual (Øverli et al. 2004b). Thus, as opposed to the inhibitory
effect of 5-HT during long-term social stress (Winberg and
Nilsson 1993b;Ho¨glund et al. 2001), elevated forebrain 5-HT
activity was associated with increased aggression in animals
subjected to short-term defeat.
As did the results for fishes, our own measurements of sero-
tonergic activity during socially stressful aggressive interactions
in reptiles led us to question the inverse relationship between
5-HT and aggression. We have consistently measured increased
serotonergic activity in both brain stem (Summers and Green-
berg 1995) and limbic regions (Summers et al. 1998, 2003b)
during aggressive interaction. The first clue that serotonergic
activity did not inhibit aggressive behavior during territorial
aggression was measured in the telencephalon of wild Sceloporus
jarrovi (Matter et al. 1998). The most aggressive territorial males
showed elevated serotonergic activity only 30 s into a fight
under field conditions. This is during the period when ag-
gression is escalating, and elevated serotonergic activity in these
aggressive males does not appear to limit the response. In fact,
it would be maladaptive if it did inhibit aggression at this time.
Taking S. jarrovi and A. carolinensis together, the changes oc-
curred over a period of between 30 s and 1 mo of social in-
teraction, and while the combat usually did not last longer than
10 min, the effects of aggression plus continuing social inter-
action on serotonergic activity were continuously changing,
with variable concentrations in dominant and subordinate
males for an entire month (Summers 2001, 2002). Temporal
variability in serotonergic activity may account for the sub-
stantial behavioral differences between aggressive dominant
males and less aggressive subordinates. Now we add to the
temporal profile (Summers 2001, 2002; Summers et al. 2003b)
preaggression levels of serotonergic activity (Fig. 2), which ap-
pear to confirm the notion that the degree of change over time
may be the most important element in the serotonergic influ-
ence on aggression (Fig. 3).
Serotonin turnover is lower in more aggressive chicks (van
Hierden et al. 2002). Like the effect of tryptophan in fish, the
serotonin precursor 5-HTP attenuated aggression in pigeons
(Fachinelli et al. 1989), and SSRIs diminish aggression in spar-
rows and pigeons (Hine et al. 1975; Sperry et al. 2003). It would
be a very useful experiment to have artificially induced inter-
actions among wild birds, much like those with the lizard S.
jarrovi (Matter et al. 1998), and measure serotonergic activity
immediately afterward.
Among mammals, rodents have clearly been demonstrated
to exhibit localized serotonergic responses to socially stressful
aggressive interactions (Blanchard et al. 1991, 1993). An elegant
experiment in rats, however, suggests that regionally specific 5-
HT release should be investigated before as well as during and
after aggression (van Erp and Miczek 2000).
Before, During, or After
Pharmacological studies, described above, suggest that changing
the level of serotonergic activity before an aggressive interaction,
even immediately before combat, changes the level of agonistic
behavior exhibited. Unfortunately, overwhelming serotonergic
systems with global application of SSRIs, serotonergic toxins,
or even specific receptor drugs does not proscribe the events
that occur before interaction that cause or inhibit aggression,
especially as most studies inhibit but do not provoke increased
aggressive behavior. Studies on the aggressive nature of nitric
oxide knockout mice suggest that reduced serotonergic activity
is the causative agent for the aggressiveness of this specifically
selected model (Nelson and Chiavegatto 2000; Chiavegatto et
al. 2001; Chiavegatto and Nelson 2003), but they are saddled
with the extra uncertainty that artificially removing the capacity
to produce a chemical messenger as important as nitric oxide
may also dramatically change other structural and chemical
elements in these mice that might be more important to ag-
gressive behavior than 5-HT. To begin to suggest a causative
role for 5-HT in aggression, specific levels of 5-HT and its
metabolites must be measured before, during, and after ag-
gressive interaction in specific brain regions associated and un-
associated with agonistic behavior. Plasma 5-HT levels have
been measured both before and after aggression in fish. Con-
trary to the expected relationship of aggression to 5-HT when
measured in the brain, but similar to findings for crayfish he-
molymph 5-HT (Huber et al. 1997), elevated plasma 5-HT in
these fish was positively correlated with aggression, suggesting
that 5-HT, at least in plasma, promoted aggression (Sneddon
et al. 2004). In another exciting study using microdialysis, ag-
gressive mice showed a clear decrease in the extracellular pool
of released 5-HT in the prefrontal cortex during a fight but
not before it (van Erp and Miczek 2000). These data suggest
that 5-HT responds to aggression but does not play a causative
role, although for most microdialysis studies, the methodology
of normalizing the data as a percent of baseline levels taken
before the treatment may obscure differences before the ag-
gression begins. In addition, the microdialysis studies in mice
clearly demonstrated the local specificity of serotonergic activity
relative to aggression. Although extracellular 5-HT levels de-
creased in the prefrontal cortex, they did not diminish in the
nucleus accumbens during aggression. These data surprised us.
One reason is that the nucleus accumbens is an important
center for motivation, a necessary component of launching an
aggressive attack or defense. Another reason is that this region
consistently exhibited serotonergic reactivity in the lizard A.
carolinensis during or just after aggression (Summers et al. 1998,
2003b; Korzan et al. 2000b; Korzan and Summers 2004). How-
ever, our data, including those presented here (Fig. 1), also
suggest that serotonergic activity is regionally specific relative
to aggressive behavior. Our results suggest that the nucleus
accumbens, as well as the medial amygdala, anterior hypo-
5-HT and Aggression 687
thalamus, septum, raphe, and locus ceruleus, exhibits lower
serotonergic activity ( ratio) in aggressive males5-HIAA/5-HT
than in their more docile counterparts (Fig. 2). The data sug-
gest, as does the prevailing hypothesis, that 5-HT inhibits ag-
gression but has this influence only in specific brain regions.
There was no correlation between aggressive propensity and
serotonergic activity in the lateral amygdala, the preoptic area
of the hypothalamus, the substantia nigra, or the ventral teg-
mental area. A conundrum remains that during or shortly after
aggressive interaction in fish, lizards, and rodents, most mea-
sures of serotonergic activity are elevated. This is especially true
in stress-responsive regions of the brain, including the nucleus
accumbens (Fig. 3). Given that both more aggressive dominant
males and less aggressive subordinate males have elevated sero-
tonergic activity during or after a fight and that dominant
aggressive males have reduced serotonergic activity before ag-
gression, the magnitude of serotonergic responsiveness is
greatest in dominant aggressive males. This suggests that sero-
tonergic activity is temporally and sequentially responsive to
both aggression and the stress that aggression engenders.
Stress
Social interactions, aggressive or not, are stressful and stimulate
regionally elevated central serotonergic activity and temporally
elevated plasma glucocorticoids. Some social interactions,
much like locomotion, however stressful initially, also have the
capacity to ameliorate or reduce stress responsiveness (Levine
1993; Emerson et al. 2000). One of the compelling questions
about 5-HT’s inhibitory role in aggression is how aggression
can be stressful while reduced 5-HT is supposed to cause ag-
gression and elevated serotonergic activity results from stressful
conditions. The results presented in Figures 1 and 2 suggest
both a solution and another problem. First, if lower seroto-
nergic activity in nuclei of aggression neural circuitry is the
basal state for potentially more aggressive males, as our data
for A. carolinensis suggest (Fig. 2), then it may play a role in
allowing aggression even though the stress of aggression itself
stimulates a rapid elevation in serotonergic activity (Fig. 3).
Recent evidence that 5-HT
3
receptors promote aggression (Ricci
et al. 2004, 2005), while 5-HT
1A
and 5-HT
1B
receptors inhibit
aggression (Saudou et al. 1994; Sa´nchez et al. 1996; Cologer-
Clifford et al. 1999; Chiavegatto et al. 2001), suggests that ag-
gression neurocircuitry centered on the anterior hypothalamus
(Delville et al. 2000; Hala´sz et al. 2002b; David et al. 2004) is
passively active when 5-HT release is low and still active during
short-term increases but blocked by chronically elevated sero-
tonergic activity. Rapid changes in serotonergic activity are not
inconsistent with the level of aggressive events as they progress
throughout the combat. By 10 min of an aggressive encounter,
serotonergic activity in stress-related regions, such as the hip-
pocampus, and nuclei of stress- plus aggression-related cir-
cuitry, such as the nucleus accumbens and medial amygdala,
are elevated in both dominant and subordinate males (Sum-
mers et al. 2003b). It is extremely important to note that the
largest change in serotonergic activity appears to occur in dom-
inant aggressive males. That suggests that although lower basal
serotonergic output does facilitate aggression, during and after
aggression the greatest serotonergic responsiveness also occurs
in dominant aggressive males (Fig. 2). Therefore, rapid and
substantial stress-induced changes in serotonergic activity do
not immediately and directly limit aggressive behavior.
Context
There is other evidence in the lizard A. carolinensis to suggest
that a change in serotonergic activity is not necessary for di-
minished aggressive behavior. Recent work applying the do-
pamine precursor L-DOPA showed a significant decrease in
aggressive behavior in a repeated trial following treatment,
when saline treatment had no effect (Ho¨glund et al. 2005).
What is surprising is that the L-DOPA treatment did not sub-
stantially affect 5-HTP, 5-HT, or 5-HIAA anywhere in the brain.
These data suggest that changing central serotonergic activity
may be sufficient to influence aggression but is not necessary.
The specific context of the experimental protocol reported
here is that we have used an indirect behavioral assessment to
determine the most vigorously aggressive and likely dominant
males in a population without actually having them interact.
This is less than ideal, and future experiments should be de-
signed to determine regional serotonergic activity in the same
animal before and after combat (when technical progress allows
it). However, we used two different tests to help us determine
males likely to be both aggressive and dominant in social rank.
These tests were based on two different premises: (1) that dom-
inant males recover from stress more quickly (Øverli et al.
2004a) and (2) that dominant males are simply more proactive,
in all behavioral activities, than subordinate males (Koolhaas
et al. 1999). A more rapid response to mates suggests a more
generally responsive male, but it also implies a possible role for
androgens in the aggressive capacity that has been examined
in so many species (Moore 1988; Bonson et al. 1994; Wingfield
1994; Knapp and Moore 1995; Wingfield et al. 1997; Soma et
al. 2000; Tokarz et al. 2002; Yang and Wilczynski 2002). It has
been suggested for A. carolinensis that reproductive state and
androgen levels may be associated with aggressive capacity
(Greenberg and Crews 1990; Lovern et al. 2001). This notion
is supported by work in hamsters that demonstrates that an-
drogenic steroids given during adolescence facilitates offensive
aggression via serotonergic mechanisms (Melloni and Ferris
1996; Melloni et al. 1997; Grimes and Melloni 2002). The SSRI
fluoxetine blocked the aggression that was stimulated by
anabolic-androgenic steroids, and there was a reduction of se-
rotonergic terminals in regions associated with aggression cir-
cuitry: the anterior hypothalamus, ventrolateral hypothalamus,
and medial amygdala (Grimes and Melloni 2002). Our work
688 C. H. Summers et al.
on A. carolinensis showed that acute testosterone modifies lim-
bic serotonergic activity (Summers et al. 2000). In contrast,
chronic testosterone administration diminishes both 5-HT and
5-HIAA levels in the rat hippocampus and increases the affinity
of hippocampal 5-HT
1A
receptors without upregulating them
(Bonson et al. 1994). These data suggest that the relationships
between androgens and serotonergic parameters are labile. In
mice that attack with a short latency, hippocampal CA
1
5-HT
1A
receptor mRNA is significantly lower than that of more docile
mice (van Riel et al. 2002). In these mice, there were no regional
5-HT
1A
differences in CA
3
, dentate gyrus, or cortex. Our data
also suggest a regionally specific influence of aggressive dis-
position on serotonergic activity, and we also did not measure
a difference between aggressive and unaggressive males in the
CA
3
region of the hippocampus (Fig. 2). We suspect that the
increased serotonergic activity that we measure in the hippo-
campus and other regions, such as the nucleus accumbens and
medial amygdala, during aggression has more to do with stress
than with aggression (Winberg and Nilsson 1993a; Summers
2002; Summers et al. 2003b). Of course, the two are not un-
related; the stress hormone corticosterone both stimulates
(Summers et al. 2000, 2003c) and is stimulated by 5-HT release
(Winberg et al. 1997a) while playing an important adaptive
role regulating the energy necessary to cope with natural stress-
ors like injury and predation as well as social aggression. In
addition, corticosterone has been demonstrated to stimulate
aggressive behavior when applied to the attack area in the an-
terior hypothalamus (Kruk et al. 1998; Kruk 2002) via fast
positive feedback (Kruk et al. 2004); the area appears to respond
similarly to arginine vasopressin (AVP; Ferris et al. 1999). Our
results suggest that the role of the anterior hypothalamus in
aggression is evolutionarily conserved and important in reptiles.
Conclusions
Despite the fact that globally acting serotonergic drugs will
modify aggressive behavior, our data, along with those of other
investigators, suggest that not all 5-HT levels and releases are
directly related to aggression. It is activity in specific regions
that appears to be responsible for the serotonergic influence
on aggression. The neural circuitry regulating aggression ap-
pears to be evolutionarily conserved in vertebrates. In addition,
it does not appear that aggression-induced stimulation of sero-
tonergic activity limits further aggression, at least not in the
short run. Because serotonergic activity is correlated with both
aggressive behavior (negatively) and stress (positively), it seems
likely that serotonergic functions are contextually significant,
especially considering that stress necessarily accompanies ag-
gression. Perhaps regionally specific serotonergic activity is a
part of the mechanism that provides context to socially stressful
situations. It is likely that in regions such as the hypothalamus,
low serotonin levels permit the actions of other agents, such
as AVP (Delville et al. 1996; Ferris 1996, 2000; Ferris et al. 1999)
and corticosterone (Kruk et al. 1998; Haller et al. 2000a, 2000b,
2001; Hala´sz et al. 2002a, 2002b), to effectively elicit aggression.
Long-term elevation of baseline 5-HT levels effectively inhibits
aggressive behavior, but brief spikes in serotonergic activity in
limbic regions associated with stress do not influence aggression
at all. While 5-HT is a broadly distributed neuromodulator
with extensive behavioral effects, its influence appears to be
locally felt in a specifically context-dependent manner.
Acknowledgments
This article results from the Society for Experimental Biology
(SEB) symposium entitled “Integration of Behaviour and Phys-
iology.” We would like to thank Kath Sloman, Rod Wilson, and
Kathleen M. Gilmour for organizing and leading the sympo-
sium at the SEB annual meeting in Edinburgh, Scotland, March
29–April 2, 2004. This research was funded by National Insti-
tutes of Health grants P20 RR15567, R03 MH068303 (G.L.F.),
R03 MH068364 (M.J.W.), and 1 F31 MH64983 (W.J.K.).
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