Serotonin and Aggression

Abstract

The neurotransmitter serotonin (5-HT) has been implicated in the modulation of aggression in animals and humans. A longstanding dogma that aggression and serotonergic activity are inversely related has to be abandoned in light of many new findings. Trait and state aggression are differentially regulated by the 5-HT system and different 5-HT receptors seem to be involved. Of the 14 different 5-HT receptors, the 5-HT(1B) receptor, particularly the postsynaptically located 5-HT(1B) heteroreceptor, plays a highly selective role in the modulation of offensive aggression. We are still far from understanding the complex role played by the serotonergic system in the modulation of a complex set of behaviors like aggression.

Full text

382
Ann. N.Y. Acad. Sci. 1036: 382–392 (2004). © 2004 New York Academy of Sciences.
doi: 10.1196/annals.1330.022
Serotonin and Aggression
BEREND OLIVIER
Department of Psychopharmacology, Utrecht Institute of Pharmaceutical Sciences, and
Rudolf Magnus Institute for Neuroscience, Faculty of Pharmaceutical Sciences,
Utrecht University, Utrecht, the Netherlands
Yale University School of Medicine, Department of Psychiatry,
New Haven, Connecticut, USA
ABSTRACT: The neurotransmitter serotonin (5-HT) has been implicated in the
modulation of aggression in animals and humans. A longstanding dogma that
aggression and serotonergic activity are inversely related has to be abandoned
in light of many new findings. Trait and state aggression are differentially reg-
ulated by the 5-HT system and different 5-HT receptors seem to be involved.
Of the 14 different 5-HT receptors, the 5-HT1B receptor, particularly the
postsynaptically located 5-HT1B heteroreceptor, plays a highly selective role in
the modulation of offensive aggression. We are still far from understanding the
complex role played by the serotonergic system in the modulation of a complex
set of behaviors like aggression.
KEYWORDS: serotonin; aggression; 5-HT1B receptor; 5-HT1A receptor; animal
models
INTRODUCTION TO THE SEROTONERGIC SYSTEM AND
5-HT RECEPTORS
The 5-HT system in the central nervous system contains a limited, but well-
defined number of serotonergic cells. The cell bodies (soma) are mainly located in
the mid- and hindbrain1 and serotonergic neurons project both to rostral and caudal
areas of the brain.2 In particular, it is thought that the rostral projections play a big
role in the involvement of the serotonergic system in the pathology of various psy-
chiatric disorders.
The serotonergic system is complex and, in the last decade, an enormous volume
of new findings have dramatically changed the simple concept of the neuron–neu-
rotransmitter–receptor axis. At present, 14 different serotonin receptors can be dis-
tinguished within the serotonin receptor family: 5-HT1A, 5-HT1B, 5-HT1D, 5-ht1E,
5-ht1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-ht5A, 5-ht5B, 5-HT6, and 5-HT7.
The various receptors are neuroanatomically localized at different sites in the
CNS.3 Thus, 5-HT1A receptors are abundant in the hippocampus, septum, neocortex,
Address for corrrespondence: Department of Psychopharmacology, Utrecht Institute of Phar-
maceutical Sciences and Rudolf Magnus Institute for Neuroscience, Faculty of Pharmaceutical
Sciences, Utrecht University, Sorbonnelaan 36, 3584CA Utrecht, the Netherlands. Voice: 31 30
2533529; fax: 31 30 253 7900.
b.olivier@pharm.uu.nl

383OLIVIER: SEROTONIN AND AGGRESSION
and raphe nuclei; 5-HT1B/1D receptors show high density in the pallidum and substan-
tia nigra and 5-HT2C receptors have a high occurrence in the hypothalamus, pallidum,
substantia nigra and, particularly, in the choroid plexus. 5-HT2A receptors are mainly
localized in the neocortex, whilst 5-HT3 receptors are common in the substantia gelat-
inosa. The distribution of 5-HT4 receptors is widespread in the striatum, olfactory tu-
bercle, nucleus accumbens, globus pallidus, and substantia nigra,4 whilst 5-HT5
receptors are predominantly located in the cerebral cortex, hippocampus, habenula, ol-
factory bulb, and cerebellum.5 5-HT6 receptors receptors are present in the brain, and
5-HT6 mRNA is strongly expressed in olfactory tubercles, striatum, nucleus accum-
bens, hippocampus, olfactory bulb, and cerebral cortex.6 Finally, 5-HT7 receptors are
present in the hippocampus, cerebral cortex, hypothalamus, thalamus and amygdala.6
5-HT1A receptors are localized presynaptically on the cell bodies and dendrites
(so-called somatodendritically) of 5-HT neurons in the raphe nuclei and postsynap-
tically on many nonserotonergic neurons. 5-HT1B (and 5-HT1D) receptors are also
localized pre- and postsynaptically; presynaptically, 5-HT1B receptors are localized
as so-called autoreceptors on the axon terminals,7 whilst postsynaptic 5-HT1B recep-
tors are heteroreceptors localized at the axon terminals of non-serotonergic neu-
rons.8 All other 5-HT receptors are presumably localized postsynaptically.9
Besides all these receptors the serotonergic transporter (5-HTT) plays an impor-
tant role in the modulation of serotonergic neurotransmission. The 5-HT transporter
is localized both at the terminal portion of the axon and at the cell body of the 5-HT
neuron.10–13
The 5-HT receptor family is part of two extended gene superfamilies; the G-pro-
tein–coupled receptor superfamily and the ligand-gated ion channel superfamily.
The 5-HT1,2,4,5,6 and 7 receptors are linked to the modulation of either adenylate cy-
clase or phosphoinositol turnover via G proteins, whereas 5-HT3 receptors modulate
ion channels.
The activity of a serotonergic neuron is presumably regulated via two kind of auto-
receptors (5-HT1A and 1B) and the 5-HT-transporter.14 When the neuron fires, the neu-
rotransmitter is released from its terminals and activates for some time all available 5-
HT receptors. In order to regulate the firing and the release of serotonin, several mech-
anisms are around to modulate the firing of the 5-HT neuron. First, 5-HT-transporters
in the synaptic terminals, but also at the cell bodies and the dendrites of the 5-HT neu-
rons, bring 5-HT back into the neuron via an uptake mechanism. This process, 5-HT
reuptake, is a very important mechanism of a cell to restore its resting condition in or-
der to be able to fire again and to avoid overstimulation of receptors. A second mech-
anism contributing to cessation of cell firing and stopping release is activation of the
5-HT1B autoreceptor at the level of the synaptic terminals, leading to a direct inhibition
of 5-HT release. A third mechanism is constituted by the somatodendritic 5-HT1A au-
toreceptors, which, upon activation, directly inhibit cell firing and, consequently, sero-
tonin release. Whether the endogenous serotonin necessary for this inhibition derives
from release of 5-HT from the somatodendritic areas themselves or originates from
terminals from neighboring cell in the raphe nuclei is not completely clear yet.14 The
interplay of these three processes leads to an apparently highly fine-tuned system of
firing patterns of the serotonergic neurons, which are needed to modulate the various
and extensive functions in which this neurotransmitter is involved.
The 5-HT1B receptor, previously called 5-HT1B in rodents and 5-HT1Dβ in other
species, including man, is now called r5-HT1B and h5-HT1B, respectively.15 The 5-

384 ANNALS NEW YORK ACADEMY OF SCIENCES
HT1B receptors from different species have a large similarity and corresponding func-
tions, but the pharmacology displayed by the rodent and nonrodent versions is quite
different, although this difference is only due to one amino acid in one transmembrane
domain of the 7 TM receptor. No functional differences in 5-HT1B autoreceptors and
heteroreceptors have been reported, but some genetic variation in the h5-HT1B recep-
tors has been found16; a mutation in the third transmembrane domain has an allele fre-
quency of 2% and leads to a receptor with a deviant pharmacology from the wild type
(98% allele frequency). The functional consequences of these kind of genetic varia-
tions are unknown, but potentially could cause disturbances in CNS functioning.
IS SEROTONIN INHIBITORY IN AGGRESSION?
The big dogma in the relationship between serotonin and aggression is that 5-HT
inhibits aggression, a conclusion mainly derived from studies in which serotonin lev-
els in the brain were decreased by neurotoxic agents like pCPA or 5,7-DHT, which
deplete serotonin from serotonergic cells. Such an inverse relationship between 5-
HT and aggression has been found in animals and humans, although in humans mea-
surements of 5-HT activity were based on CSF levels of the main metabolite of se-
rotonin, 5-HIAA. Notwithstanding severe criticisms of this parameter, for many
years it was the only measure in humans reflecting (indirectly) the functional status
of the 5-HT system. In animals, 5-HT and its metabolite 5-HIAA can be measured
directly in the brain and it could be assumed that the inverse relationship between
functional serotonergic activity and aggression should easily be established. Howev-
er, several contradictory results have been found and there have even been reports of
a positive relationship between 5-HT and aggression. In humans aggression is asso-
ciated with suicidal behavior, and both seem to be associated with low serotonergic
function, although it is possible that both phenomena are independently regulated
(see Mann17 for an extensive discussion on the neurobiology of suicidal behavior).
Measurement of contents of 5-HT and 5-HIAA in postmortem brain tissue and
determining a turnover rate from these two parameters was originally described to
be lower in aggressive vs. nonaggressive mice.18 Successively measuring CSF sam-
ples in humans more or less supported this serotonergic hypofunction.19–21 Howev-
er, this 5-HT hypofunction or deficiency trait more recently has been associated with
impulsivity and risk-taking behavior rather than aggression per se.17 A causal rela-
tion between 5-HT activity and aggression or impulsivity cannot be derived from
static measurements of 5-HT or 5-HIAA measurements in brain tissue or CSF-fluid.
A functional role of serotonergic neurons in the initiation, execution, and stopping
of aggression22,23 still has to be established, although some progress has been made
using in vivo microdialysis techniques in freely moving (aggressive) animals. This
technique however, still lacks sufficient resolution because sample time (minutes) is
still of a different magnitude than the actual behavior (seconds). Van Erp and
Miczek24 measured extracellular serotonin (and dopamine) release in 10-min sam-
ples in the nucleus accumbens (Nac) and prefrontal cortex in rats, before, during and
after a 10-min aggressive interaction with a male conspecific. During the agonistic
interaction no detectable change in 5-HT release was found in the NAc, but 5-HT
levels were already decreased during fighting in the prefrontal cortex. After the con-
frontation, 5-HT levels in the PFC remained lowered (compared to pre-confrontation

385OLIVIER: SEROTONIN AND AGGRESSION
baseline) for at least 1 hour, whereas 5-HT in the NAc was not affected. Dopamine
levels were enhanced in both brain areas after (but not during) the agonistic confron-
tation. However, 5-HT levels were decreased in the NAc of rats that have been con-
ditioned to fight at a specific time each day over a 10-day period.25 In the latter
experiments, heart rate and dopamine release were concurrently measured and both
were raised in anticipation of the fight. Apparently, the actual performance of ag-
gression can be dissociated from the anticipation of a fight, where dopamine plays
an important role in the physiological and behavioral sequels around the perfor-
mance and anticipation of aggression, whereas serotonin seems to be particularly
related to termination of aggression.
Measuring electrophysiological events happening in the serotonergic neurons
during the performance of aggressive behavior would be very helpful in unraveling
the precise role of the serotonergic system, but this seems technically not yet feasi-
ble. Moreover, the serotonergic system is not made up of one homogeneous mass of
cells, but is differentiated; the dorsal and median raphe nuclei projecting to the dif-
ferent areas of the forebrain are the most prominent sources of serotonergic neurons
innervating areas involved in the initiation, performance, and termination of aggres-
sive behavior. Interestingly, no systematic studies have been performed thus far to
delineate the role of the different serotonergic cell groups in various aspects of ag-
gression, although local lesions or local application of drugs in the dorsal or median
raphe nuclei have been performed. It is highly unlikely that all serotonergic cell
groups are involved, and selective blockade or activation of individual cell groups in
determining its role in aggression would be very fruitful.
A recent approach to unraveling the role of the 5-HT system in aggression is
studying the differences between high-aggressive and low-aggressive individuals,
as has recently been pursued by Koolhaas’s group.26 Their argument was based on
the assumption that the individual level of aggression of a rat (offensive aggression)
is part of an individual coping strategy of the animal and thus an important indicator
of a trait-like behavioral and physiological response pattern. In their extensive stud-
ies on the endophenotypes of high-aggression and non-aggressive rodents, seroto-
nin was also studied. In contrast to the existing theory of inverse relationship
between 5-HT activity and aggression, a positive correlation was found between the
level of trait-like aggression (high or low) and basal CSF concentrations of 5-HT
and 5-HIAA.27 Moreover, levels of 5-HT and 5-HIAA after microdialysis in the
frontal cortex did not differ between endophenotypes. Apparently, normal offensive
aggression is positively related to serotonergic neuronal activity, whereas an inverse
relationship probably exists between 5-HT activity and impulse-like violent
aggression.22
Thus a general pattern emerges where trait and state aggression are probably dif-
ferentially regulated by the 5-HT system (and also other systems), although much
more research is needed to substantiate this hypothesis.
SEROTONIN RECEPTORS
The 14 different 5-HT receptors and the 5-HTT enable the unraveling of the func-
tion and contribution of the different receptors in various aspects of aggression. To
date, ligands are available for most receptors, including (partial) agonists and antag-

386 ANNALS NEW YORK ACADEMY OF SCIENCES
onists, although for some receptors no adequate tools are available, particularly for
recently described receptors (5-HT5,6,7,1e,1f). Since 5-HT1 and 2 receptors have been
studied since the 1980s, research on the role of these receptors in aggression is most
abundant.
5-HT1 Receptors
Clinically, only one partial 5-HT1A receptor agonist, buspirone, has been avail-
able and its effect on aggression in humans is not very well described,28,29 nor does
it appear very promising. Preclinically, an extensive range of 5-HT1A receptor ago-
nists and antagonists are available.30 Moreover, prototypic agonists like 8-OH-
DPAT, flesinoxan and buspirone or antagonists like WAY100,635 have been used in
aggression studies in animals.
Although practically all studies report anti-aggressive effects of 5-HT1A receptor
agonists in various species, these effects are not specific in the sense that anti-ag-
gressive effects occur at doses that also compromise non-aggressive elements of the
behavioral repertoire.31–33 5-HT1A receptor antagonists have no intrinsic effects on
aggression, but are able to antagonize the anti-aggressive effects of 5-HT1A receptor
agonists.33–35 There is conflicting evidence whether 5-HT1A receptor agonists exert
their anti-aggressive effects via pre- or postsynaptically located 5-HT1A receptors.
Lesions of the raphe nuclei, by removing 5-HT1A somatodendritic autoreceptors, did
not prevent the anti-aggressive effects of eltoprazine36 or 8-OH-DPAT.37 However,
eltoprazine is a mixed 5-HT1A,1B receptor agonist and its anti-aggressive effects in
5,7-dihydroxytryptophan-lesioned rats might be due to activation of postsynaptic 5-
HT1B receptors. In the study by Nikulina and Miczek37 remaining 5-HT1A autore-
ceptors (there was a limited depletion of serotonin in this study, suggesting a consid-
erable number of intact 5-HT neurons after the 5,7-DHT insult) may be responsible
for this effect. Infusion of 8-OH-DPAT and eltoprazine into the dorsal raphe
nucleus38 reduced aggressive behavior in rats, but concomitantly reduced social in-
terest and increased inactivity, indicative of a nonselective reduction of aggression.
TFMPP, a more selective 5-HT1B receptor agonist than eltoprazine, had no effect un-
der these conditions, suggesting that the nonspecific reduction of aggression after 8-
OH-DPAT and eltoprazine was caused by activation of serotonergic autoreceptors in
the dorsal raphe nucleus. When these drugs were infused into the lateral ventricle,
8-OH-DPAT had no anti-aggressive effects, whereas eltoprazine and TFMPP had a
very selective anti-aggressive effect. This indicates that postsynaptic 5-HT1A recep-
tors are not involved in the aggression-modulating effects of 5-HT1A receptor ago-
nists and that the specific reduction in aggression is induced by activation of
postsynaptically located 5-HT1B receptors.39 A strong argument against a specific
role of 5-HT1A receptors in specific modulation of (offensive) aggression derives
from studies where aggression was evoked by electrical stimulation in the hypothal-
amus of rats.40 This kind of extremely aggressive behavior towards a male conspe-
cific was not at all sensitive to 5-HT1A receptor agonists like 8-OH-DPAT,
buspirone, and flesinoxan,41 even at extremely high doses. Apparently, by directly
stimulating the neural substrate activating aggressive behavior, the role of the 5-
HT1A receptor is minimal or nonexistent, whereas 5-HT1B receptor agonists
(TFMPP and eltoprazine) dose-dependently and behavior-specifically reduced this
kind of “violent” aggression.

387OLIVIER: SEROTONIN AND AGGRESSION
On the other hand, certain 5-HT1A receptor agonists from the benzodioxopiper-
azine class30 seem to exert anti-aggressive effects via presynaptic 5-HT1A autore-
ceptors.35,42 Activation of presynaptic 5-HT1A autoreceptors leads to decreased
firing of the 5-HT neuron and decreased release of 5-HT at the synaptic level. It
seems unlikely that such a general reduction in 5-HT turnover that affects all (pre-
and postsynaptic) 5-HT receptors, would lead to such a specific reduction in aggres-
sion. Moreover, chronic administration of 5-HT1A receptor agonists leads to down-
regulation of 5-HT1A autoreceptors and subsequent increased cell firing and
enhanced 5-HT release. On a chronic base the acute anti-aggressive effects would
subside and even enhanced aggression might develop after chronic treatment. No
chronic studies with 5-HT1A receptor agonists have been reported, but they are
clearly needed to understand the acute vs. chronic effects of 5-HT1A receptor ago-
nists on aggression (TABLE 1).
The 5-HT1B receptor has been the focus of interest in the development of clini-
cally relevant anti-aggressive agents, the so-called serenics.43 The 5-HT1B receptor
terminology has been confusing. The 5-HT1B receptor in rodents and humans, al-
though exerting a similar function, differs in an essential amino acid in the ligand-
binding domain of the receptor that leads to a dramatic difference in the pharmaco-
logic sensitivity and specificity (REF). Agonists for the rodent (r5-HT1B) 5-HT1B re-
ceptor are anti-aggressive and exert a serenic profile,43 defined as a dose-dependent
decrease in offensive aggression, without concomitant sedation or motor or sensory
impairment that could explain the anti-aggressive effect. The early serenics (e.g.,
TABLE 1. Summary of effects of psychoactive agents with selectivity for subtypes of
serotonin receptors
5-HT
Principle
Resident-
Intruder
Mouse
Resident-
Intruder
Rat
Maternal
Aggression
Rat
Brain-
Induced
Aggression
Rat
Muricide
Rat
Defensive
Behavior
Mouse/Rat
1A agonist 0䉬䉬 䉬 00 0
1A antagonist 0 0 0 0 0 0
1B agonist +++ ++ 0
1B antagonist 0 0 0 0 0 0
2A agonist 䉬䉬䉬 −䉬−
2A antagonist 䉬䉬 −0䉬−
2C agonist 䉬䉬 䉬 −− −
2C antagonist 䉬䉬 䉬 −− −
3-agonist 0 0 −−0−
3-antagonist 0 0 0 −0−
Reuptake blockade 䉬䉬䉬 00 0
0 = no effect on aggression; 䉬 = non-specific reduction in aggression; + = specific reduction
in aggression (serenic effect); − = not tested
Data are based on our own published and unpublished work (summarized in Olivier
et al.31,41,43).

388 ANNALS NEW YORK ACADEMY OF SCIENCES
fluprazine, DU28412, DU 27725, eltoprazine, batoprazine)43 were mixed 5-HT1A/
1B receptor agonists, leaving the 5-HT1A receptor still as an option for mediating
(part of) the anti-aggressive effect. However, more recently synthesized 5-HT1B re-
ceptor agonists including, for example, anpirtoline, CP-94,253 and zolmitriptan,
were far more selective for this receptor and showed a similar, highly specific anti-
aggressive effect, both in aggressive residential mice and in mice made more aggres-
sive via low-doses of alcohol or social instigation.44–46
5-HT1B receptor knockout mice47 show enhanced aggressive behavior,47–50 but
due to the low baseline aggression level of the genetic background (129Sv) strain,
the “enhanced” aggression in the KO mice was still low. More recent studies50–52
have implicated the 5-HT1B receptor in impulsivity regulation, rather than offensive
aggression per se,3153 suggesting that the specific anti-aggressive effects of 5-HT1B
receptor agonists are modulated via postsynaptic 5-HT1B receptors. Such postsyn-
aptic 5-HT1B receptors are located as heteroreceptors on nonserotonergic neurons
(including dopaminergic, cholinergic, and GABAA-ergic neurons). These hetero-
ceptors, when activated by 5-HT, inhibit ongoing behavior, including aggression.
Thus, the 5-HT1B receptor agonist inhibits those “aggression or impulsivity” modu-
lating neurons, and removing the postsynaptic 5-HT1B receptor (via null mutation of
the 5-HT1B receptor gene) removes this “brake,” thereby facilitating various behav-
iors related to impulsivity, hyperactivity, and aggression.54 Based on the “hyperag-
gressive” 5-HT1B receptor knockout mouse and the anti-aggressive effects of 5-
HT1B receptor agonists, suggestions can be made that administration of 5-HT1B re-
ceptor antagonists might lead to facilitation of aggression. However, all such antag-
onists appear silent, comparable to 5-HT1A receptor antagonists, probably indicating
that under normal, physiological conditions the serotonergic tone at postsynaptic 5-
HT1B receptors is not that strong.
5-HT2 Receptors
Although 5-HT2 ligands have been synthesized and tested in aggression, these
compounds are extremely difficult to typify on their specificity in aggression (for a
thorough review see Miczek et al.23). The available agents for 5-HT2A and 2B recep-
tors are not that specific and, when tested, show anti-aggressive effects at similar
doses that exert sometimes severe (sedating) side effects.31,55 There is some evi-
dence that 5-HT2A receptor antagonists (e.g., risperidone) inhibit aggressive behav-
ior in patients with varying diagnoses, including depression and schizophrenia.
However, no specific evidence thus far points to a selective contribution of any 5-
HT2 subtype receptor to aggression.
5-HT Transporter
Since the 5-HTT is only located on the serotonergic neuron (both in the synaptic
terminal and the somatodendritic areas), its function is directly related to the feed-
back mechanisms involved in 5-HT neuron firing and 5-HT release. Because SSRIs
block the uptake of 5-HT, the net effect after acute SSRI administration is probably
a mild increase in 5-HT release at the synaptic terminal. After chronic administra-
tion, leading to downregulation of somatodendritic 5-HT1A autoreceptors, and hence
lowered inhibition of cell-firing and enhanced terminal 5-HT release, 5-HT is prob-

389OLIVIER: SEROTONIN AND AGGRESSION
ably far more strongly enhanced than after acute administration. Therefore, acute,
but certainly chronic, administration of SSRIs should lead to inhibition of aggres-
sion, on the basis of the hypothesis that activation of postsynaptic 5-HT1B receptors
mediates anti-aggressive effects. Clinical data seem to support this hypothesis.56–58
However, SSRIs are not known as mainstream treatment for aggressive pathology in
humans. Preclinically, acute administration of SSRIs has anti-aggressive effects, al-
though not in a behaviorally specific way.31 This is not too surprising because the
enhanced 5-HT activates all 5-HT receptors, and thus a plethora of effects might be
expected. Chronic administration of SSRIs leads to contrasting effects: to reduction
in mice,59 but to increases in rats.60 Mutant mice lacking the 5-HTT are less aggres-
sive than their wild types,61 confirming that chronically elevated 5-HT release inhib-
its aggression.
Although infrequent reports emerge on the possible role of other (5-HT3,4,6,7)
serotonergic receptors, it is unclear whether, and what role they might play.
CONCLUSIONS
The serotonergic system in the CNS has complex interactions with many, if not
all other neurotransmitter systems in the brain. Its localization, distribution, and
amazing receptor diversity makes it an appealing system for modulatory aspects in
many basic behaviors, including food and water intake, sexual behavior, and aggres-
sion among others. Notwithstanding decades of research into the putative role of the
serotonergic system in aggression, no clear picture emerges. Aggression seems de-
pendent on state or trait to be involved in either the performance or the termination
of aggressive behaviors. The present technology appears not developed enough to
give answers to these questions. Application of drugs, and particular selective
ligands for certain subtype receptors seems a more promising approach to unraveling
the role of 5-HT in aggression. The (postsynaptic) 5-HT1B and, to a lesser extent, the
5-HT1A receptor seem to play a prominent role, at least in rodents, in the modulation
of (offensive) aggression.
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