The roles of serotonin and dopamine in reactive and ...

UNIVERSITY OF AMSTERDAM – BRAIN AND COGNITIVE SCIENCE – COGNITIVE TRACK

The roles of serotonin anddopamine in reactive and

proactive aggressionA literature thesis in partial fulfilment of the

requirements for the degree of Master ofScience

Jonathan Krikeb, BSc, 1006518012 June 2015

Supervisor: Co-assessor:

dhr. prof. dr. C.K.W. de Dreu dhr. dr. M.P. Lebreton

Krikeb, J., Serotonin and dopamine in predator-prey aggression

Abstract:

Aggression is often linked to violence but this is not a necessary connection. Aggression could

also be motivating choices for economic-decision making. The question of what leads to aggression

is what this paper will address as it discusses the bi-modal classification of aggression: proactive and

reactive. These two classes will be linked to a new predator-prey research paradigm that separates

the greed and its proactive tendencies, from the fear and its reactive actions. This, as well as a few

other economic games, will be linked to the wide scope of research into aggressive violent

behaviour, that is mostly based on clinical cases, as well as decision-making research that is founded

on the idea that focuses on impulsive behaviour as it has been linked to aggression in the past. These

past findings have also found correlations between serotonin hypoactivity, and also dopamine

hyperactivity, in cases of irregular aggressive behaviour. We will attempt to establish how activities

of the serotonergic and the dopaminergic circuitries parallel aggression in predator and prey type of

interactions.

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Table of Contents

1. Introduction.......................................................................................................................................4

1.1. Aggressive behaviour.................................................................................................................4

1.2. Bi-modal classification of aggression.........................................................................................6

1.3. Aggression networks..................................................................................................................8

2. Experimental paradigms..................................................................................................................10

2.1. Aggressive behaviour in economic games...............................................................................10

2.2. The predator prey game..........................................................................................................11

2.2.1. Greed and calculated aggression in the predator............................................................14

2.2.2. PFC and goal-oriented behaviour....................................................................................14

2.2.3. Fear and reactive aggression in the prey.........................................................................16

2.2.4. Amygdala and fearful behaviour......................................................................................16

2.3. Aggressive behaviour in current research on neurotransmitters............................................18

2.4. Impulsive behaviour in experiments........................................................................................20

2.5. Experimental paradigms of impulsivity....................................................................................21

2.5.1. 5-CSRT..............................................................................................................................22

2.5.2. Go/no-go.........................................................................................................................22

2.5.3. SSRT.................................................................................................................................23

2.5.4. Reversal learning.............................................................................................................23

2.5.5. Delayed reward...............................................................................................................23

3. Serotonin.........................................................................................................................................23

3.1.1. Molecule..........................................................................................................................24

3.1.2. Different receptors in different brain regions..................................................................25

3.1.3. Tryptophan depletion......................................................................................................27

3.1.4. Tryptophan supplementation..........................................................................................28

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3.1.5. Serotonin knockouts........................................................................................................28

3.1.6. Specific agonists/antagonists and neurotoxins................................................................29

3.2. Serotonin and impulsivity........................................................................................................29

3.3. Link between serotonin research to predator and prey behaviours........................................30

4. Dopamine........................................................................................................................................35

4.1.1. Molecule..........................................................................................................................35

4.1.2. Different receptors in different brain regions..................................................................35

4.1.3. Parkinson’s and L-dopa....................................................................................................37

4.1.4. Other manipulations to dopamine..................................................................................37

4.2. Dopamine and impulsivity.......................................................................................................38

4.3. Link between dopamine research to predator and prey behaviours.......................................38

5. Interactions between serotonin and dopamine...............................................................................39

6. Discussion........................................................................................................................................40

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1. IntroductionAn attack to gain more resources by someone who has an abundance of them does not have the

same motivation as the defensive reaction of the prey, in this same scenario, that defends its limited

resources. In this sort of predator against prey interaction, two types of aggression come into play:

proactive and reactive. Reactive aggression has been widely studied, often in context of impulsive

aggression, while the literature on proactive aggression is more scarce. In light of the research into

the motives behind these behaviours, and how this is reflected in terms of neurotransmitters, this

paper will follow past studies and look at how the key neurotransmitters serotonin and dopamine

interact in these two different types of aggression, namely predator and prey.

1.1. Aggressive behaviour

Aggression traditionally requires a conflict between at least two parties that may compete for

the same object, physical or otherwise (Nelson & Trainor, 2007).Since aggression and violence often

go hand-in-hand, the results of aggressive behaviour often lead to damage, which is often physical,

and therefore aggression is dangerous and not always the best choice in conflict circumstances. It

does have an evolutionary role in food, or mate, acquisition, or protection, as well as inner

motivations such as fear, greed, anger or even pleasure. When these motives lead to aggressive acts

that hurt, or injure others, then we consider aggression as unaccepted in our current human society

– war or criminal acts such as robbery or battery (de Almeida, Ferrari, Parmigiani, & Miczek, 2005).

There is a wide selection of literature available on aggression, much of it is composed of

psychological research focusing on clinical and criminal cases such as: workplace aggression (Hills &

Joyce, 2013; Piquero, Piquero, Craig, & Clipper, 2013; S. F. Smith & Lilienfeld, 2013), domestic

aggression (George et al., 2001; Soler, Vinayak, & Quadagno, 2000), alcohol and drug related (Anholt

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& Mackay, 2012; Badawy, 2003; de Almeida et al., 2005; George et al., 2001; Gowin, Swann, Moeller,

& Lane, 2010; Skara et al., 2008), and arson (Linnoila, Virkkunen, & Scheinin, 1983). All this research

shows how ingrained in human society aggression is and how destructive it could get, thus

necessitating a deeper understanding of the motives behind it.

In order to better understand aggression and its motives, different classification systems were

established. In this paper, as the introduction suggests, we will focus on a binary classification

system. Two other systems were suggested in previous studies as well. First, as described both by

Siegel and Victoroff (2009) and Umukoro, Aladeokin, and Eduviere (2013) where they divide

aggression into seven separate motivations it may originate from: fear -induced, maternal, irritable,

inter-male, sex-related, predatory, and territorial. However, in the case of humans, these are not as

clear-cut cases as they are in the animal world.

A third classification is offered by separating the motives into four categories: stress and fear-

induced, anger and frustration-induced, instrumental offence, and pleasure motivated. However, in

both cases of the alternative classifications, we could collapse them into a bimodal classification

system that is easier to apply for humans, where the study of aggression is complex as it is. An

example used by Siegel and Victoroff (2009) is a gang fight where the mix of planning, inter-male

dominance, and emotions of anger or fear interact to spark the fighting. In such a bimodal

classification, one side would be predatory, goal-oriented, calculated, instrumental, proactive,

premeditated aggression. This would be contrasted with a reactive, impulsive, protective, defensive,

hostile aggression (Malone et al., 1998; McEllistrem, 2004; Nelson & Trainor, 2007; Siegel &

Victoroff, 2009; Umukoro et al., 2013; Weinshenker & Siegel, 2002). Whereas the former has very

little literature looking into it, the latter sort is more related to pathological aggression, and often

associated in research with reduced levels of the neurotransmitter 5-hydroxytryptamine (5-HT or

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serotonin) (Anholt & Mackay, 2012; Badawy, 2003; Berman, Tracy, & Coccaro, 1997; Booij et al.,

2010; Brown et al., 1982; Brown, Goodwin, & Ballenger, 1979; Crockett, Clark, Lieberman, Tabibnia,

& Robbins, 2010; Crockett, Clark, & Robbins, 2009; Crockett, Clark, Tabibnia, Lieberman, & Robbins,

2008; Daw, Kakade, & Dayan, 2002; de Boer & Koolhaas, 2005; Linnoila et al., 1983; Perez, 2012;

Wetzler, Kahn, Asnis, Korn, & van Praag, 1991). These studies relate many pathologies related to

impulse control including drug and alcohol addiction, pyromancy, suicidal tendencies, as well as

repeated violent crimes, to observed low levels of serotonin. While it is important to notice that

these studies find correlation, and not causation, we will examine throughout this paper the role of

serotonin in aggression and impulsive behaviour.

Fig. 1. Bi-modal classification of aggression and where neurotransmitter research has been involved so far.

1.2. Bi-modal classification of aggression

As suggested above, this paper will focus on a bimodal classification of aggression, namely:

predatory, and reactive. This bimodal classification is discussed in in depth in a few articles

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(Chichinadze, Chichinadze, & Lazarashvili, 2011; Malone et al., 1998; McEllistrem, 2004; Siegel &

Victoroff, 2009; Umukoro et al., 2013; Weinshenker & Siegel, 2002). Reactive aggression is closely

related in the literature to affective defence, or aggression (McEllistrem, 2004; Weinshenker &

Siegel, 2002). This type of aggression is much more studied in comparison to the other, predatory

type (Siegel & Victoroff, 2009). In animal models, it is easily classified since it is expected in cases of

invasion to personal space or ingression on food reserves. This aggression is also easily measured in

terms of strong sympathetic nervous system activation (Weinshenker & Siegel, 2002). This suggests

that this type of aggression is instinctive, and therefore impulsive – there is no consideration of the

long-term results, only immediate elimination of the current threat. Implicitly this links this

aggression to emotions: anger, anxiety, and fear, and thus to the limbic system. The impulsive aspect

will be discussed further since it is a core concept in criminal and clinical studies of aggression.

The other type of aggression of interest in this paper is offensive, predatory aggression. Amongst

animals this is usually the manner in which a predatory animal hunts and consumes a prey animal.

However, our focus should be, in order to compare to human cases, on intraspecies aggression such

as climbing up the social hierarchy amongst groups of monkeys where one aims to dominate

(Chichinadze et al., 2011). A human example could be, for instance, a burglary – ingression into

another’s property in order to obtain gain illegal possession of property. On a larger scale this could

be the preying of a strong nation on a weaker, less resourceful one. This type is under-studied and

while it may interact with the reactive aggression, does not rely on the same mechanisms

(McEllistrem, 2004; Umukoro et al., 2013; Weinshenker & Siegel, 2002). For starters, there is a lack

of sympathetic arousal in the predatory aggressors. Additionally, feelings, if they play a role at all,

lead to pleasure or satisfaction, as opposed to fear or anger involved in defensive acts. In this

manner, it is possible to observe the most striking difference between the types of aggression:

reactive defence is unmeasured, it lashes out (Weinshenker & Siegel, 2002). In economic terms, the

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investment would be un-proportional to the risk. In contrast, predatory, calculated, aggression, as

the latter term suggests, involves very thought-out allocation of resources – both manner and

magnitude become significant, whereas in defence they are not.

Weinshenker and Siegel (2002) discuss the advantage, for the sake of research, of distinguishing

the psychopaths. These individuals, who have difficulty relating to emotions, comprise a large part of

prison populations and their motivations are more alike to predatory in nature, as opposed to

impulsive violent offenders. Interestingly, instrumental aggression is also linked to dominance

(Chichinadze et al., 2011). The brain mechanisms involved in planning and executive function, are

the ones that would also be instrumental in predatory action. This coincides with data linking

advantage of serotonin enhanced performance leading to domination among monkeys whereas

depletion of the neurotransmitter, associated with impulsivity, does not have the same effect

(Berman et al., 1997).

In the following sections we will follow the research paradigms implemented in impulsive

behaviour and aggression research in economic decision-making. This will lead to the predator-prey

paradigm, devised by de Dreu, Scholte, van Winden, and Ridderinkhof (2014), that establishes, using

an asymmetrical game, the roles of proactive and reactive aggression.

1.3. Aggression networks

Aggressive behaviour is closely linked to social behaviour, both because of the context in which

aggression takes place, and also due to the brain network involved in aggressive behaviour. This

circuitry involves: the amygdala, and the rest of the limbic system; the periaqueductal gray (PAG);

the hypothalamus; and sections of the prefrontal cortex (PFC) (Nelson & Trainor, 2007). These

regions are also innervated by the raphe nuclei where serotonin is produced in the brain

(Martinowich & Lu, 2008). The connection with serotonin has been also observed in the clinic where

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drugs that interact with the serotonergic system are used to treat psychiatric cases that affect social

behaviour. The social context is important to consider whenever research using animal models is

interpreted into a human environment. An example to consider is the discovery of the “sham-rage”

phenomenon in a cat upon the stimulation of the hypothalamus (McEllistrem, 2004) - this does not

translate so neatly into a human equivalent situation.

In later parts of this paper, we will establish links between these networks and aggressive

behaviour in various experimental settings.

Fig. 2. Networks of neurotransmitters in the brain. The serotonergic system is in green and the dopaminergic system is inred. The origins of molecule production are seen in the table and their interaction can be seen in both amygdala and the

prefrontal cortex (PFC) (adapted from Doya, 2002).

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2. Experimental paradigms

2.1. Aggressive behaviour in economic games

In economic settings, an aggressive investor puts more money into play and takes bigger risks

(Afza & Nazir, 2007; Nazir & Afza, 2009). Investments of this nature seem more impulsive. However,

aggressive behaviour could also translate into offensive behaviour; initiating purchases and trying to

increase assets. This behaviour is a type of calculated aggression. This highlights the difficulty in

separating the two types of aggression in economic decision-making.

In economic experiments, using different games to model decision-making, defection or

punishment is often conceptualised as aggression (Crockett, 2009). For instance, in the prisoner’s

dilemma game, the peaceful solution would be cooperation where both sides gain together

maximally, however, the aggressive solution, where both defect, is the Nash Equilibrium. These two

behaviour choices alternate depending on the type and frequency of interaction between the parties

(Kassinove, Roth, Owens, & Fuller, 2002; Martin, Juvina, Lebiere, & Gonzalez, 2013). This applies

similarly to the ultimatum game. In this game, one side decides how to share an initial sum and the

other side can decide whether to reject the offer, thereby leaving both participants with nothing, or

accept it, and share as agreed. If one is aggressive, he would reject an unfair (or perhaps even fair)

offer. If the player is cooperative, he would accept the offer, as long as he gets something (Mehta &

Beer, 2010). Rejecting an offer in the ultimatum game can be perceived as a type of punishment.

This however, was challenged by Crockett et al. (2008), as we will further discuss later. Finally, it

would be of the biggest interest to separate instrumental (predatory) aggression, of the form where

one side wishes to break the status-quo and increase its winnings, from reactive (prey) aggression,

where one side fends off the predator, at cost to itself, in order to maintain the current equilibrium.

We can relate both of these behaviours to market, and social, behaviours such as a buy-out of a

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company or going bankrupt so as not to be bought-off. We have found two experimental paradigms

that separate these different aggressive behaviours and elucidate their underlying mechanisms

(Crockett, Clark, and Robbins, 2009; and de Dreu, Scholte, van Winden, and Ridderinkhof, 2014).

2.2. The predator prey game

Ideally we would like a game that creates a distinction between the two groups of aggressors:

goal-oriented, predatory aggressors, versus the prey-like, reactive (defensive) aggressors. This in

addition to manipulations of subjects in terms of neurotransmitters and stress, as well as tasks

involving impulse control and aggression questionnaires; all of which will be addressed in a following

section.

We need to first question the motives for being aggressive as either predator, or prey. We will

start with the prey. We can look at an individual, or a group, as belonging to a prey category when

they wish to maintain a certain status-quo – wishing to keep a job, or ownership of a company or a

piece of land. Therefore, for someone in that situation to turn to aggression, to attack or invest

money and resources, implies that they are compelled by fear of someone altering the current state

of things. In lab conditions there are various games to notice this reaction. Looking at a prisoners’

dilemma game as an example, this fear of defection of the other party could motivate one to defect

as well. This is a reactive defence behaviour. In an alternative version of the prisoners’ dilemma, a

withdrawal option is added to the game (Insko, Schopler, Hoyle, Dardis, & Graetz, 1990). This option

can distinguish between two fear reactions: those who turn to impulsivity and defect, or those who

are calculated, maintain their calm, and withdraw.

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Table 1. Prisoner's dilemma standard payoff matrix (adapted from Wood et al., 2006).

Table 2. Prisoner's dilemma alternative payoff matrix (adapted from Insko et al., 1990).

In contrast, the predator, a greedy, goal-driven, individual or group, would wish to revisit the

current situation. This party would like to earn more than it currently does, or own another’s land or

property. It is important when comparing to animal models to consider only intraspecies preying, as

it is in humans. For that purpose of increasing winnings the predator would invest, and risk, its

resources. Therefore seemingly it is greed that motivates the predator in its choices when it decides

to aggress against a docile counterpart. Similar to the case described for the prey, the predator

would also defect in the prisoners’ dilemma game. Unlike the prey, the predator would do so in the

hope that the other party cooperates, and thus the predator will maximise its personal gain.

The two psychological motives have been taken apart in different paradigms in order to study

only fear, or only greed, and what decisions they would lead to. The chicken game uses a similar

payoff scheme to the prisoners’ dilemma, only in this scenario a tie is a loss thus only defection

would lead to a win and fear is dominant (Bornstein & Gilula, 2003). The assurance game, in

contrast, encourages cooperation since that would lead to the biggest payoff to both parties and

therefore is meant to exemplify only greed (Bornstein & Gilula, 2003).

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A\B Coop DefectCoop 20\20 0\30Defect 30\0 10\10

A\B Coop Withdraw DefectCoop 57\57 48\48 33\66

Withdraw 48\48 48\48 48\48Defect 66\33 48\48 39\39


Table 3. The assurance game group payoff matrix with the independent variable being the number of investors inevery group (adapted from Bornstein & Gilula, 2003).

Table 4. The chicken game group payoff matrix with the independent variable being the number of investors in everygroup (adapted from Bornstein & Gilula, 2003).

To contrast these games, a predator-prey game captured both motives in an asymmetrical game

and thus allowed both types of aggressive behaviours to come into play (De Dreu et al., 2014). In this

game, one party, the predator, wins by investing more than the prey, thereby taking all the prey’s

leftover sum after investments. During the same investment, the other party, the prey, can only

keep their leftover sum if they amassed a sufficient defence – they invested equal to or more than

the predator (De Dreu et al., 2014). This design, in its intra-group version (De Dreu, Giffin, Krikeb,

Prochazkova, & Columbus, 2015), is easy to equate to warfare between nations over territory or

resources. One side, with predatory motives, is aggressing by taking action and investing in order to

win what resources the prey party has. In reaction to this aggression, the other side defends itself,

investing of its own resources to protect the remaining resources. As we will discuss later, this

defence could be entirely impulsive and therefore likely to be exaggerated, or it could be also

calculated, with an added long-term effect view. Accordingly, brain regions involved in greed and

fear are different and so it has been observed that the two parties have different brain activations:

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A\B 0 1 2 30 135\135 45\120 45\105 45\901 120\45 120\120 30\105 30\902 105\45 105\30 105\105 15\903 90\45 90\30 90\15 90\90

A\B 0 1 2 30 45\45 45\120 45\105 45\901 120\45 30\30 30\105 30\902 105\45 105\30 15\15 15\903 90\45 90\30 90\15 0\0


the amygdala and superior frontal gyrus (anatomically part of the PFC) activations in the predators

were dampened by oxytocin whereas the prey’s amygdala was active regardless of condition (De

Dreu et al., 2014). Following this, we would expect a different pattern of neurotransmitter activity to

support these activations.

2.2.1. Greed and calculated aggression in the predator

In a predator-prey game, any predator that plays the game, instead of simply keeping their initial

endowment, becomes an aggressor. It is this type of aggression that is under-studied and we would

like to better highlight what sort of neural mechanism is potentially motivating it, as opposed to the

impulsive aggression that is under the main study focus in relation to reduced levels of 5-HT (de

Almeida et al., 2005; Takahashi, Quadros, de Almeida, & Miczek, 2011). In a cat, predatory behaviour

has been initiated by stimulation of the perifornical lateral hypothalamus, the ventral part of the

PAG, and the ventral-tegmental area (VTA) where dopamine is produced (Siegel & Victoroff, 2009).

The goal of this aggression, being something with a benefit past the act itself, is in contrast to

the reactive defence which lacks foresight. As Siegel and Victoroff (2009) point out, this planning

leads to the base assumption that the cerebral cortex is involved in the predatory aggression,

whereas it is not necessary for prey defence.

2.2.2. PFC and goal-oriented behaviour

To go further in depth into the decision-making of the predator, we need to examine some brain

regions that are associated with planning. First, the prefrontal cortex (PFC) is mainly associated with

top-down cognitive function, goal-oriented behaviour, temporal control, and attention control

(Agnoli & Carli, 2012; Narayanan, Land, Solder, Deisseroth, & DiLeone, 2012; Winstanley, Theobald,

Dalley, Cardinal, & Robbins, 2006). It is therefore connected to impulse-control and conditions

involving its control such as suicidal tendencies, attention deficit hyperactivity disorder, and

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obsessive compulsive disorder (OCD). The PFC also has projections from the thalamus via the basal

ganglia, where dopamine is a key neurotransmitter (Agnoli & Carli, 2012). This aspect has been

studied using the 5 choice serial reaction time task (5-CSRT) with rats where it was shown that a

bilateral lesion of the medial PFC or dorsomedial (including the superior frontal gyrus) lead to

increased impulsivity. The aspect of motor inhibition, associated with action planning, was studied

by Rubia et al. (2005) using a go/no-go task. In their paper, they found decreased activation in the

right orbital and the inferior PFC following tryptophan depletion in humans using functional

magnetic resonance imaging (fMRI). Their results also indicate no real change in mood nor any

actual effect on the inhibitory control during the task (Rubia et al., 2005). Impulse-control is also

related to loss-aversion, that has also been a proposed task of the PFC (Murphy et al., 2009).

Further properties of the PFC we would need to inspect are the type of neurons to be found and

which neurotransmitters activate them. Pyramidal neurons, as well as GABAergic ones, in the medial

PFC (mPFC) express 5-HT1A receptors. While serotonin endogenously inhibits mPFC pyramidal

excitation, systemic 5-HT agonists administered to rats tend to excite the VTA projecting cells (Lladó-

Pelfort, Santana, Ghisi, Artigas, & Celada, 2012). The VTA, in the midbrain, also projects back to the

PFC using dopamine as input (Narayanan et al., 2012). Both D1 and D2 receptors are expressed in the

PFC. Narayanan et al. (2012) showed that D1 disruption interferes with temporal control while its

stimulation enhances efficiency in a fixed-interval timing task. These dopaminergic neurons could be

innervated by serotonergic projections coming from the raphe nuclei to both VTA and PFC where in

addition to 5-HT1A, also 5-HT2A receptors are present (Pehek, Nocjar, Roth, Byrd, & Mabrouk, 2006).

Pehek et al. (2006) showed that 5-HT2A blocking in the PFC results in dopamine blocking thus indeed

linking the dopaminergic to the serotonergic system. Both these neurotransmitter systems will come

into further focus later on and it is important that it first understood that they play a significant role

in the PFC’s activity.

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2.2.3. Fear and reactive aggression in the prey

A prey in the game, similar to a mother defending her offspring, would resort to an affective

defence behaviour (Siegel & Victoroff, 2009). This defence behaviour is observed despite the

anonymity of the players (De Dreu et al., 2015). This fear of danger leads to a reaction whose

purpose is eliminating the threat. It is for this reason that this action, often aggressive, is impulsive;

it does not require any calculation beyond the threat and therefore likely to be out of proportion for

the assurance of its success. Additionally, strong impulses can induce fear (Apter et al., 1990),

showing us that also in this mechanism there may be a feedback loop. The fear reaction is strongly

based in the limbic system (Post et al., 1998; Yoon, Fitzgerald, Angstadt, McCarron, & Phan, 2007).

Moreover, research into defensive rage found that by direct stimulation of the medial hypothalamus

or the dorsolateral region of the PAG, this defensive reaction could be initiated (Nelson & Trainor,

2007; Siegel & Victoroff, 2009).

In terms of neurotransmitters, impulsive behaviour is mainly linked to serotonergic hypoactivity

(de Almeida et al., 2005; McEllistrem, 2004; Siegel & Victoroff, 2009; Takahashi et al., 2011;

Weinshenker & Siegel, 2002) as well as irregularities in the dopaminergic system (Rogers, 2011; E. S.

Smith, Geissler, Schallert, & Lee, 2013). It is important to realise that the reactive aggression, largely

based on sympathetic activation, could be accompanied by calculated aggression, which would

mitigate the impulsive reaction and allow planning to take place beyond the immediate effect of

removing the threat (McEllistrem, 2004; Weinshenker & Siegel, 2002). This could be compared to a

territorial war where the defender has realised that conquest of some of the attacker’s territory

would be beneficial.

2.2.4. Amygdala and fearful behaviour

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The limbic system in general, and the amygdala specifically as part of it, include the brain

structures classically associated with emotions (Post et al., 1998; Yoon et al., 2007). This system is

also believed to be a part that belongs to the early stages of brain evolution. Of highest relevance to

this paper, it is associated with fear and anxiety (De Dreu, 2012; Saha, Gamboa-Esteves, & Batten,

2010). Irregular activation of the amygdala is associated with many anxiety disorders, such as PTSD

(Nardo et al., 2010; Pagani et al., 2012) and different phobias (see: Caseras et al., 2010; Klumpp,

Angstadt, Nathan, & Phan, 2010; Yoon et al., 2007). Crucially for this paper is its relation to decisions

instructed by fear as the dominant emotion. As de Dreu and colleagues (2014) found in their study

using the predator-prey game, the amygdala was more strongly activated among the prey,

contrasted with the predator, when making their investment decisions. This, in addition to the faster

reaction time, indicates the decision was more instinctive.

At this point, we need to explore the projections of the amygdala in order to understand what

the roles of dopamine and serotonin, as neurotransmitters in that region, may be. First, the

amygdala, as part of the limbic system, projects to the hypothalamus, and the PAG (Siegel &

Victoroff, 2009). This links the amygdala to the aggressions that we know could be initiated by the

hypothalamus.

Serotonin, produced in the raphe nuclei, influences the amygdala through many projections

from the dorsal raphe nuclei. Past studies also showed that 5-HT1A and 5-HT1B receptors are

associated with anxiety and depression (Saha et al., 2010). Saha et al. (2010) further elaborated on

this by showing the large number of neurons marked for 5-HT1B receptors and relatively low number

with 5-HT1A receptors in the amygdala. This will become more significant later when we discuss the

receptors’ separate roles.

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In addition to serotonergic function, also dopamine is instrumental in fear response. There are

many efferent fibres to the amygdala from the VTA (Rezayof, Hosseini, & Zarrindast, 2009) as well as

bidirectional interaction with the substantia-nigra (E. S. Smith et al., 2013). These two areas are

both part of the dopamine-dominant reward-system. The effects of dopamine are quite substantial

on the amygdala. For instance, dopamine depletion prevents memory formation related to fear

through amygdala function, whereas specific restoration of dopamine to the VTA –amygdala

pathway reverses the effect (Li, Dabrowska, Hazra, & Rainnie, 2011). Specifically D1, and not D2,

receptors are crucial for this process. D1 receptor antagonist SCH23390 has been shown to eliminate

learning entirely by blocking the long-term potentiation (LTP) process from occurring in

glutamatergic neurons (Li et al., 2011). Also the role of dopamine will be further explored later in

this paper.

2.3. Aggressive behaviour in current research on neurotransmitters

While this paper is focused on the decisions that derive from both reactive, as well as predatory

aggression, there is little research that focuses on the neurotransmitters that are involved in both of

these decisions in humans. In several studies, based mostly on the ultimatum game, the type of

aggression that matches punishment was correlated to serotonin levels using a tryptophan depletion

experiment (Crockett et al., 2010, 2009, 2008; Crockett, 2009). In other research, aggressive

behaviour is measured in other ways. The lifetime history of aggression scale is used by health

workers to establish an individual’s trait aggression based on interviews and clinical history (Nelson

& Trainor, 2007). Better suited to this paper is the aggression questionnaire the was developed by

Vitiello, Behar, Hunt, Stoff, and Ricciuti (1990) that separates the questions to predatory and

affective classifications. In their unique study they found that almost every subject had a mixture of

the two characteristics. The more predatory individuals tended to have a higher IQ score, while the

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reactive children had a higher prevalence of schizophrenia. Malone et al. (1998) have used this same

questionnaire, as well as the Overt Aggression Scale and the Global Clinical Judgements Scale and

had similar findings, yet not with the same significance.

Alternatively, the choice of violent offenders as subjects eliminates the need for objectivity

amongst the subjects (Linnoila et al., 1983). This research also led to the idea that it is not aggression

that is indicated by lower serotonin levels but impulsivity. This has been the dominant dogma for a

long period and has been the focus of many studies (Anholt & Mackay, 2012; Badawy, 2003; Berman

et al., 1997; Booij et al., 2010; Brown et al., 1982, 1979; Crockett et al., 2010, 2009, 2008; Daw et al.,

2002; de Boer & Koolhaas, 2005; Linnoila et al., 1983; Perez, 2012; Wetzler et al., 1991). Another

major data source for the 5-HT impulsivity theory comes from suicide cases; both from autopsies,

and from CSF of failed attempts. Low levels of serotonin, or its metabolite, 5-HIAA, in the latter case,

have been discovered in past studies (Dalley & Roiser, 2012). People who attempted suicide also

testify through questionnaires on possessing more impulsive tendencies.

In animal models there are different paradigms. Research focusing on the hypothalamus and the

“sham rage” phenomenon in cats was pioneering the way for future research on violence and

aggression (McEllistrem, 2004; Weinshenker & Siegel, 2002). Studies involved direct stimulation of

brain areas believed to be involved in aggression, introduction of a trespasser, or inter-male violence

in competition for dominance or a female. In these studies they either manipulate or measure levels

of different neurotransmitters. These are mostly measures of violence, as well as being in lab

settings. This conditions make it difficult to translate to human environment (Nelson & Trainor,

2007).

Also studied, albeit with a little less focus, are the increased levels of dopamine in aggression

(Boureau & Dayan, 2011; Daw et al., 2002; de Almeida et al., 2005; Seo, Patrick, & Kennealy, 2008;

19


Vukhac, Sankoorikal, & Wang, 2001) and norepinephrine (NE, also called noradrenaline) (Anholt &

Mackay, 2012; Chichinadze et al., 2011; Higley et al., 1996; Perez, 2012), and the effects of gamma-

Aminobutyric acid (GABA) (Anholt & Mackay, 2012; de Almeida et al., 2005; Gowin et al., 2010; Seo

et al., 2008). However, as previously written, this paper will restrict itself to serotonin and dopamine.

2.4. Impulsive behaviour in experiments

In a large part of available research on aggression, the focus is on criminal and clinical cases, and

not on aggressive choices. These cases come under the impulsive sort of aggression in a large part of

the cases (exception of psychopaths who show no emotion and therefore seem to be more

predatory (Perez, 2012)). For instance, Linnoila, Virkkunen, and Scheinin (1983) found a link between

serotonin and impulsive aggression amongst violent criminals. They went on to suggest that what

serotonin hypoactivity indicates is impulsive behaviour, and not aggression in general.

Dalley et al. (2011) define impulsive behaviour as “the tendency to act prematurely without

foresight”. They also clearly distinguish between impulsive and compulsive behaviour, despite the

oftentimes seen confusion of the terms. Yet since their definition for compulsive behaviour focuses

on the undesired consequences of the actions (p. 680), we could bundle both behaviours as having

unforeseen (negative) results. Therefore, we would follow from studies that examine impulsivity to

conclusions concerning rash decisions that lead to negative results.

A majority of the clinical data on human impulsive behaviour comes from suicide cases, a case of

extreme impulsivity (Dalley & Roiser, 2012). This link is also explored in many other studies (Crockett

et al., 2010; Dalley, Everitt, & Robbins, 2011; Higley et al., 1996; Malone et al., 1998; Mehta & Beer,

2010; Umukoro et al., 2013). The problem with many such studies is that the focus is on clinical or

criminal cases which pre-assigns the subjects and places them under a certain category – impulsive

individuals. A better scenario is using healthy individuals, or animals, to test impulsivity under

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certain conditions. The conditions could be induced stress, hormonal manipulations, or

neurotransmitter manipulation, as some examples. The manner in which the impulsivity, or

aggression, could be tested is using questionnaires, such as the lifetime history of aggression scale,

or decisions made in tests such as the 5-choice serial reaction time task, delay discounting task, stop-

signal task, or go/no-go task. In questionnaires, individuals must testify about their own behaviour.

In the tasks, impulsivity is decided based on the ability to learn where waiting can lead to reward.

Using these methods it is possible to observe how healthy subjects react to manipulations and

therefore allow for determination of causation. We will review these tasks later as they will be used

to draw some conclusions concerning the roles of serotonin and dopamine in impulsive behaviour

among healthy subjects.

2.5. Experimental paradigms of impulsivity

What we learn from past experiments on aggression is that it is necessary to extract the

cognitive mechanism leading to it, which is, to a large extent impulsive behaviour (Dalley, Mar,

Economidou, & Robbins, 2008; Homberg, 2012; Kiser, Steemers, Branchi, & Homberg, 2012). It is a

type of behaviour that is more conspicuous in clinical cases related to gambling, alcoholism, drug

abuse, depression, and schizophrenia (Badawy, 2003; Booij et al., 2010; Dalley et al., 2011; Daw et

al., 2002; Doya, 2002; Linnoila et al., 1983; Okai, Samuel, Askey-Jones, David, & Brown, 2011; Rogers,

2011; Scholes et al., 2007; Umukoro et al., 2013) but while it does enlighten us as to some

particularities of the system, we are not interested in the pathological case, but in the healthy. It is

healthy people who mostly interact in predator-prey situations.

Impulsivity could be examined using questionnaires or different tasks. Questionnaires include:

the Barratt impulsiveness scale, the urgency, premeditation, perseverance, and sensation seeking

impulsive behaviour scale, Behaviour Scale, the Impulsiveness Venturesomeness and Empathy

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Questionnaire, and the Lifetime History of Impulsive Behaviours (Dalley et al., 2011; Dalley & Roiser,

2012). There are several tasks that are often used in the lab, some only fit for animals, and some for

both animals and humans, that are used to examine impulsive behaviour. Even though action

suppression is mostly the manner of study, and impulsive action does not use the exact same

mechanism as impulsive choice, it is a useful study tool since the mechanisms interact along with the

serotonergic and dopaminergic systems (Dalley et al., 2011). We will now briefly introduce some of

the more common methods.

2.5.1. 5-CSRT

The 5-choice serial reaction time task involves the animal initiating the trial and then waiting for

one of five cues to light up. A press before the light has turned on is deemed impulsive and results a

5 second timeout. A press on the button under the correct light, once it has turned on, results in a

reward food-item. An incorrect press, or no choice at all, are incorrect choices and result in a

timeout as well. The goal of this task is to learn to suppress a response in order to gain a reward

(Dalley et al., 2011; Dalley & Roiser, 2012).

2.5.2. Go/no-go

A Go/no-go, or stop-signal, task can have a human or an animal version to it; in the human

version the reward is often simply a smiley face while in the animal model version the reward is a

food item. In this task the subject must press the button on ‘go’ trials upon the presentation of a

cue. In ‘no-go’ trials the subject must avoid pressing the button when the cue is given (Dalley &

Roiser, 2012). This task combines the effects of learning – subjects learn during the task itself how to

respond to the cue, and relearning; thereby fighting the impulse to act on what has been learnt

previously for the ‘go’ trials in order to succeed in the ‘no-go’ trials.

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2.5.3. SSRT

The stop signal reaction time task models inhibition of motor control – the ability to stop an

action that has already been initiated. It is similar to the go/no-go task only here all trials are ‘go’

trials until a ‘stop’ signal is given at which point subjects must stop responding (Dalley et al., 2011).

Crucially, reaction times for the responses are taken so it can be compared between trials after a

‘stop’ signal has been given and thus observe readjustment. Despite the similarities in the tasks,

different manipulations affect the results of SSRT and go/no-go differently (Dalley et al., 2011).

2.5.4. Reversal learning

In a reversal learning task subjects are conditioned to respond to a specific conditioned stimulus

and ignore a second stimulus. Once this conditioning is established, the subjects are asked to switch

the reactions between the stimuli – act on the second and ignore the first (Homberg, 2012). This task

can be practised both with humans, as well as with animals, even though, according to Homberg

(2012), it is not entirely clear whether the two employ the same brain mechanism for the task. This

is another paradigm of learning and suppression of action.

2.5.5. Delayed reward

A delayed reward, or delayed discounting task, constructs a situation where the subjects face a

choice between a small reward now and a larger reward later. The manipulations could be either on

the size of the reward or the length of the delay (Dalley & Roiser, 2012). In animals, the delay is

measured in seconds and the reward is food. In humans, the design involves a hypothetical choice of

monetary reward that spans between minutes and years. This paradigm has a clear focus on

impulsive choice since the strictly logical choice is always the larger reward.

3. Serotonin

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Serotonin, or 5-HT, is a well-studied neurotransmitter that has been associated with mood,

survival, social behaviour, sleep, brain plasticity, impulsivity, and mental illness (Benningfield &

Cowan, 2013; Blier & El Mansari, 2013; Dalley et al., 2011, 2008; Dalley & Roiser, 2012; Gellynck et

al., 2013; Homberg, 2012; Jouvet, 1999; Kiser et al., 2012; Lovinger, 2010; Martinowich & Lu, 2008;

Navailles & De Deurwaerdère, 2011; Roberts, 2011; Rogers, 2011; Scholes et al., 2007; Takahashi et

al., 2011). Our focus in this paper is on impulsive (choice) and aggressive behaviour as they are

linked to altered serotonin levels. Brown et al. (1979) are the first to find a negative correlation

between serotonin, based on 5-HIAA concentrations in CSF, and aggressive behaviour in humans. In

another study, both aggression and low levels of serotonin are correlated with suicide attempts

(Brown et al., 1982). In another lane of research, Linnoila et al. (1983) suggest, based on their results

that separate impulsive offenders and those who were conscious and calculated in their actions, that

low levels of serotonin are an indication of impulsive behaviour. A problem with this conclusion is

that they decided according to the offence itself who was premeditated and who was not (Berman

et al., 1997). It seems however, that despite the problems this study may present, studies that

examined the influence of alcohol on aggression, do find that certain individuals with a tendency for

violence will be more prone to it following the ingestion of alcohol and this could stem from the

alcohol’s effect on brain serotonin levels – i.e. it depletes them (Badawy, 2003). These findings

correlate with the idea that the correct food supplementation could eliminate, or reduce, aggressive

behaviour (Badawy, 2003).

3.1.1. Molecule

5-HT is produced in the raphe nuclei that sit in the mesencephalon (brainstem) (Martinowich &

Lu, 2008). It is a simple monoamine molecule, much like many other neurotransmitters such as:

dopamine, melatonin, epinephrine, and norepinephrine. 5-HT is derived from L-tryptophan, one of

the basic amino acids (Folk & Long, 1988; Kiser et al., 2012; McEllistrem, 2004). 5-HT has a major

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central metabolite, 5-hydroxyindoleactic acid (5-HIAA), and the most reliable method to examine the

presence of serotonin in the human brain is looking for it in a sample of cerebrospinal fluid (CSF)

(Brown et al., 1979).

3.1.2. Different receptors in different brain regions

Serotonin seems to have appeared early in our evolution and thus, being an important molecule,

it presents the highest number of receptors in the brain. These divide into ionotropic, which allow

ion transfer upon ligand binding, and metabotropic, which start a signalling chain within the cells

when the ligand binds. Accordingly they have different functions (Gellynck et al., 2013; Kiser et al.,

2012; Martinowich & Lu, 2008).

Serotonin is infamous for its effects following the ingestion of 3,4-

methylenedioxymethamphetamine (MDMA), which inhibits the reuptake of the neurotransmitter

back into the presynaptic neuron from the synaptic cleft by competing with it, and other

monoamines, for their reuptake transporters (SERT – serotonin reuptake transporter, and DAT –

dopamine reuptake transporter) (Benningfield & Cowan, 2013; Rubia et al., 2005). It also inserts

itself into the presynaptic neuron and induces release of more serotonin into the synaptic cleft. This

leads to social disinhibition and therefore MDMA is a very popular for recreational use. These effects

are similar to those that form the basis of antidepressant drugs, that also have the same effect of

saturating the synapses with serotonin, either through blocking reuptake or through inducing

increased production (Blier & El Mansari, 2013; Martinowich & Lu, 2008). The effects on social

behaviour are the important effects we need to keep in mind in order to understand the role of

serotonin.

Selective serotonin reuptake inhibitors (SSRIs) are the current antidepressants of choice among

clinicians (Blier & El Mansari, 2013; Crockett et al., 2009; Dalley & Roiser, 2012; Kiser et al., 2012;

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Martinowich & Lu, 2008). SSRI drugs are agonists of the 5-HT1 receptors family (Takahashi et al.,

2011). The higher concentrations of 5-HT are believed to have beneficial effects on social behaviour

generally even though that in the case of major depression, a common mental disorder, the low

levels of serotonin are not necessarily the cause (Blier & El Mansari, 2013). However, even with only

partial support linking the low levels of serotonin to aggression and major depression, increasing the

levels of 5-HT is often beneficial.

To counteract the effects of aggression, similar to antidepressants, there are drugs that activate

only a subset of the serotonin receptors. There are 16 different genes encoding 5-HT receptors (Kiser

et al., 2012) and various drugs work with different specificity on these receptors. These drugs are

tested mostly in experiments using animal models to examine their effects. De Boer and Koolhaas

(2005) examine some compounds that act as agonists and antagonists to 5-HT1A and 5-HT1B family

receptors. The former acts as an autoreceptor on 5-HT neurons, as well as a postsynaptic receptor

on pyramidal and GABAergic (inter)neurons (Lladó-Pelfort et al., 2012), that reacts differently to

different drugs according to its location. For example, S-15535, a benzodioxopiperazine, acts as an

agonist to 5-HT1A when it is on the presynaptic neuron and as an antagonist when it is on the

postsynaptic one (de Boer & Koolhaas, 2005). It has a similar effect as other pharmacological agents

in reducing aggressive behaviour, for instance: repinotan, 8-OHDPAT, ipsapirone, and some others.

Unlike these other compounds, S-15535 does not affect other aspects of non-aggressive motor

behaviour (de Boer & Koolhaas, 2005). These other effects could occur due to several reasons: a

higher dose is needed, or the non-selective activation of other receptors. This sort of study highlights

the difficulty in assessing the specific role of a specific receptor. Despite this, there are many other

studies doing so and we will look into some more of them.

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Selective antagonists of 5-HT1A and 5-HT1B indeed demonstrate blocking of the attenuating

aggression effects if given alongside S-15525, while having no effect by themselves. Specifically

related to the amygdala function, the effects of 5-HT1A receptor deficit seems to lead to anxiety

whereas its over-expression leads to aggressive behaviour (Saha et al., 2010). This is contrasted with

5-HT1B receptors whose over-expression restricts aggressive behaviour while their rat knockout

models show increased aggression (Saha et al., 2010). To contrast the actions of 5-HT1A from 5-HT2

and 5-HT3, it was shown by Stein, Davidowa, and Albrecht (2000) that a 5-HT1A agonist decreases the

firing rate of neurons in the amygdala while 5-HT2 and 5-HT3 agonists resulted an increase in firing

rate. Moreover, research on the different 5-HT2 receptors leads to different results based on the

specific location of action, as opposed to global infusion of a drug, and that is in addition to the

effect of the drug being agonist or antagonist (Homberg, 2012). In that review, Homberg (2012)

states that 5-HT6 “univocally contribute[s]” to impulsivity (p. 230) however it receives little mention

elsewhere. In addition to the amygdala, also the presence of 5-HT1A receptors in the PFC has been

addressed. Additionally, there are functional links between the OFC and the basolateral amygdala

that influence decision making (Winstanley, Theobald, Cardinal, & Robbins, 2004).

Interestingly, there is no hypersensitivity of 5-HT receptors observed in aggressive individuals

(Wetzler et al., 1991). However, aggressive individuals do have different ratios of 5-HT receptors

expressed in the brain (de Almeida et al., 2005).

3.1.3. Tryptophan depletion

One manipulation that can be done in studies specifically oriented at the effects of 5-HT is using

an acute tryptophan depletion paradigm. In the studies using this paradigm, participants drink a

liquid that contains a concoction of different concentrations of amino acids besides tryptophan

(control group drinks the same concoction that includes tryptophan as well). Based on previous

27


studies analysing rat brain tissue, this leads to a sharp reduction in serotonin production (Crockett et

al., 2009). Five hours after the intake of said drink, participants normally are controlled for changes

in mood, and then are given the task and/or commence the game (Crockett et al., 2009; Wood,

Rilling, Sanfey, Bhagwagar, & Rogers, 2006). This form of research allows for a contrast between

normal and decreased systemic concentrations of serotonin to exemplify its behavioural effects.

3.1.4. Tryptophan supplementation

Similar to depletions studies, there are also tryptophan supplementation studies performed.

Tryptophan could be supplemented in an acute study (Scarnà, McTavish, Cowen, Goodwin, &

Rogers, 2005) or over a duration of a couple of weeks (Murphy et al., 2009). In either case, the

dietary supplement consists of a high level or tryptophan that should keep the enzyme tryptophan

hydroxylase, the rate-limiting enzyme in the 5-HT production, close to saturation (Murphy et al.,

2009). The increased levels of tryptophan should in turn lead to increased 5-HT levels that alter

social behaviour (Murphy et al., 2009), similar to effects of other drugs that interact with the

serotonergic system that have been previously touched upon. Other effects on mood, memory, or

attention are then controlled for before the main task is initiated.

3.1.5. Serotonin knockouts

Another manipulation that can be performed in the lab using animal models is knockout a

specific gene using viral agents and breeding. In this paper our highlight is the knockout of specific 5-

HT receptor or enzyme genes. In such knockout models the role of a specific receptor in the entire

mechanism can be assumed from the changes observed in behaviour in the knockout animals, as

opposed to the wild-type healthy controls. Examples include knockout of the 5-HT1A or 5-HT1B

receptor (Saha et al., 2010), 5-HT transporter (5-HTT) (Kiser et al., 2012), or monoamine oxidase A

28


(MAOA) which is a main serotonin catabolising enzyme (McDermott, Tingley, Cowden, Frazzetto, &

Johnson, 2009).

3.1.6. Specific agonists/antagonists and neurotoxins

Other paradigms that involve mature animals are the use of neurotoxins or specific agonists and

antagonists. For example, 5,7-dihydroxytryptamine (5,7-DHT) injected directly to the brain removes

all serotonin (Dalley & Roiser, 2012).

Some examples of agonists and antagonists are: 8-OH-DPAT is a specific 5-HT1A agonist, (±)-1-

(2,5-dimethoxy-4-iodo- phenyl)-2-aminopropan (DOI) is a 5-HT2A/2C agonist while SER082 is an

antagonist for these receptors, SB242084 is a 5-HT2C antagonist and M100907 is an antagonist

specific for 5-HT2A (Dalley & Roiser, 2012). These are just some examples of molecules used to

examine the role of specific receptors or the interactions between them. Some of these molecules

can be injected also very accurately to specific regions, while others are given globally.

3.2. Serotonin and impulsivity

Since we discussed serotonin as a key player in impulsive behaviour, we will now look at some

evidence from the lab. Dalley and Roiser (2012) address some of the past results using various

agonists and antagonists for different 5-HT receptors. For instance: a systematic administration of

DOI increases impulsivity in a delay discounting task relying on 5-HT2A mechanism. A similar result

was achieved in the 5-CSRTT using the 5-HT2C antagonist SB242084 (Dalley & Roiser, 2012). SER082, a

5-HT2A/2C antagonist, did not affect 5-CSRTT behaviour but did impact the delay discounting task by

reducing impulsive response. 8-OH-DPAT, a 5-HT1A agonist had positive results for the choice

reaction time task however it negatively affected delay discounting. 5-HT reuptake inhibitors yielded

positive results for both tasks (Dalley & Roiser, 2012). M100907, a 5-HT2A antagonist injected to the

29


PFC, and the 5-HT1A receptor agonist 8-OHDPAT, both result in blocking impulsivity in the 5-CSRTT

(Dalley et al., 2011).

These results exemplify the role serotonin has in different types of impulsive behaviour and

would suggest therefore that it is a good candidate to maintain when examining human impulsive

decision-making.

3.3. Link between serotonin research to predator and prey behaviours

Apter et al. (1990), in their paper, discuss separating impulsivity, as a character trait, from the

different psychological diagnoses available, since it seems that this is what 5-HIAA measurements

indicate. Berman et al. (1997) suggest in their discussion that a distinction between impulsive and

non-impulsive aggression be made in further research and that potential mediating factors, such as

environmental factors, be examined. This suits our bimodal classification system.

In brain circuitry terms, this goes in line with the fact that the raphe nuclei project to the

orbitofrontal cortex (OFC), and also project back to it, thus creating a feedback loop with the

serotonergic system (Roberts, 2011). The OFC is associated with depression and obsessive

compulsive disorder but additionally, along with the PFC, it is associated with top-down control,

planning, and decision-making (Dalley et al., 2011). This decision-making could be impulsive and

more leaning towards risk, while it could be more risk-aversive. It has been found that tryptophan

supplemented diet reduced risk-taking in the form of the reflection effect as well as influencing loss-

aversion (Murphy et al., 2009, in Rogers 2011). Additionally, carriers of the ss (short) allele of the 5-

HTTPLR were more sensitive to the framing effect (Tversky & Kahneman, 1981), and could be

supposed to have been more emotional in their rationalisation since a stronger interaction between

the amygdala and the PFC was observed (Roiser et al., 2009, in Rogers 2011).

30


A link between decision-making and impulsivity could be made based on the study that found

that only delayed bad outcomes were retarded by tryptophan depletion (Blair et al., 2008, and

Tanaka et al., 2009, in Rogers 2011). This delayed learning would invite further impulsive socially

inappropriate behaviour. This is also discussed by Homberg (2012), detailing the discounting of

future reward, as well as past punishment, following tryptophan depletion. The social implications of

low levels of serotonin are also evident through the iterated prisoner’s dilemma game where

tryptophan depleted subjects were less cooperative, even while playing against the quite forgiving

tit-for-tat strategy (Wood et al., 2006).

Also according to Kiser and colleagues (2012), impulsive aggression correlates with low levels of

serotonin and calculated aggression correlates with higher levels. This works well with the idea that

higher 5-HT levels are expected in socially capable individuals and therefore they are able to

perceive hostile behaviour towards them and react accordingly. This would apply in economic terms

as well when a person, or group, should feel threatened it would enact decisions to protect itself,

however, in a measured manner.

An example for the effects of increased serotonin levels was found in monkeys. In some studies

of monkeys it was shown that tryptophan supplementation led to both better social interaction, as

well as strategic aggression the led to a rise in the hierarchy (Kiser et al., 2012).

As we have described, impulsive decisions, besides violence (a poor choice of behaviour in

current society), lead to choices that have no or little foresight. Let as move from there to economic

decisions. Thus, we would expect people with lower concentrations of 5-HT to act impulsively not

only in the standard prisoners’ dilemma game, but also in the iterated version (Wood et al., 2006; Yi,

Johnson, & Bickel, 2005). These people will choose to defect also when repeated interaction plays a

role in the eventual outcome of the game and therefore we would term them as being selfish, or

31


aggressive players. The outcomes in Yi et al. (2005) show that delayed discounting correlated with

(the successful) tit-for-tat strategy, and not with random play, in the iterated game. This behaviour

indicates an inability to see the mutual benefits of cooperation as the model of reciprocal altruism of

the iterated prisoners’ dilemma suggests, especially under the tit-for-tat strategy. Interestingly, in

Wood and colleagues’ (2006) work, trait aggression is not a consequence of tryptophan depletion.

Furthermore, the results were not replicated in the second day of the study; an effect related to the

role serotonin plays in social learning – possibly after learning the game on the first day, being

depleted on the second day did not induce as strong an of an effect.

Fig. 3. Ultimatum game decision-making (based on results of Corckett et al., 2008, 2010).

An additional point was made by Crockett et al. (2008) in their study of altruistic punishment as

a tool for social behaviour. Altruistic punishment, being a punishment where one has to make an

effort, or invest of their own funds, in order to inflict (financial) pain on others, has shown success in

experimental conditions at maintaining a social norm and is believed to serve a reciprocal social

system (Fehr & Rockenbach, 2004). According to other studies, that link serotonergic activity to it,

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altruistic punishment negatively correlates to serotonin levels following tryptophan depletion,

suggesting that it is impulsive behaviour rather than calculated (Crockett et al., 2010, 2008). Crockett

and colleagues (2010, 2008), used the ultimatum game as a tool for measuring altruistic punishment.

In this game, participants could choose whether to accept offers of splitting a sum or reject them. By

accepting, both sides split the sum as agreed, while rejection means that neither side receives

anything, thus in fact being an altruistic punishment. While it is commonly believed that rejection of

unfair offers is perceived as a calculated “teaching” strategy on behalf of the responder, according to

their findings, Crockett et al. (2010, 2008) conclude that it is in fact an impulsive choice. This is based

on the significant increase in rejection of unfair offers following tryptophan depletion. They further

support this by showing worse choices made in a delay discounting task (Crockett et al., 2010). This

task demands people to choose between a small reward now or a bigger reward later (with the size

of reward and length of time delay as variables) and is amongst the common tests used to measure

impulsivity since it makes little sense to opt for the immediate reward. In Crockett and colleagues’

(2010) study, tryptophan depletion also resulted in increase in number of instant rewards chosen.

Additionally, in their discussion, Crockett et al. (2010) connect the dorsal striatum, part of the

reward system and mostly dopamine dependant, to the enjoyment of punishment (p.860).

Protective, or reactive, aggression, is most likely related to fear and therefore to the amygdala

and the rest of the limbic system. This is based on de Dreu and colleagues’ (2014) work where they

found that the subjects acting as prey made a quicker choice in their investment. This decision was

accompanied by activation of the amygdala and therefore we can call this decision a more instinctive

one. Since the amygdala carries serotonin projections as well (Homberg, 2012; Kiser et al., 2012;

Saha et al., 2010), excitement in the amygdala is likely to involve, amongst other neurotransmitters,

also serotonin action. If we can observe increased activation then we can also assume a higher firing

rate of the 5-HT2 as well as 5-HT3 (Stein et al., 2000). This can lead also 5-HT1B activation but that

33


should reduce aggression (Saha et al., 2010). Therefore, our expectation would be 5-HT1A activation,

that we would expect to correlate with anxiety, but that should decrease activity levels across the

amygdala (Stein et al., 2000). Once again we are confronted with the intricacy of the system.

Siegel and Victoroff (2009) discuss the suppressing effect serotonin has on reactive aggression

through 5-HT1A activation in the medial hypothalamus or in the PAG. However, they indicate that

through the 5-HT2 receptor activation in the PAG, limbic system, and the hypothalamus, reactive

aggression is initiated. This links fear and aggression through the serotonergic system.

Increased activity in the superior frontal gyrus is associated with impulse control as well as

calculated behaviour (De Dreu et al., 2014). Decreased levels of activity follow tryptophan depletion

in healthy humans (Rubia et al., 2005). These two findings interact neatly to form a picture of

calculated decision-making in the PFC.

From a conscious logical perspective it is interesting to wonder why would the predator

aggressor attempt an offence to begin with since generally speaking, the defender increases its

levels of aggression often to the extent that the predator loses the conflict and therefore from the

logical standpoint, the foresight should be that initiating an offensive is the wrong move. Rogers

(2011) indicates that there is little research looking into risky choices that lead to bigger rewards and

serotonin but part of it is related to delay discounting being disturbed by tryptophan depletion that

has been previously discussed. Interestingly, probabilistic discounting is not diminished by the

depletion of tryptophan. These are both examples of behaviour that could be paralleled to predator

behaviour. To further support this effect of 5-HT deficiency, an experiment with macaques

demonstrated that switching from risky choice to safe choice demands a lower variance for the pay-

offs following tryptophan depletion, further suggesting that calculated aggression is not as

premeditated as we assume.

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All the evidence from the research on serotonin suggests that it is a necessary component of

intelligent decision making. We can hypothesise that a potential prey will become one when they

are with low levels of serotonin and one that is already a prey will invest excessively as it is the

impulsive choice. We can further hypothesise that a predator with low serotonin levels does not

exist.

4. Dopamine

4.1.1. Molecule

Dopamine, another monoamine neurotransmitter, is often studied for its effects on fine

procedural memory, working memory, reward circuit, addiction, and motor skills in relation to

Parkinson’s disease (Doya, 2002; Lovinger, 2010; Navailles & De Deurwaerdère, 2011; Okai et al.,

2011; Segura-Aguilar et al., 2014; Wise, 2009). It is also the major focus of research into the reward

circuitry in the brain and how it affects both addiction and reinforcement learning (Daw et al., 2002;

Glimcher, 2011; Volkow, Wang, Fowler, Tomasi, & Telang, 2011). It is produced from tyrosine in

dopaminergic neurons of the VTA and the substantia-nigra (SN) that project to the striatum mainly

(Brichta, Greengard, & Flajolet, 2013; Dalley & Roiser, 2012; Ikemoto, 2010; Scholes et al., 2007;

Wise, 2009). The former is related to the reward mesolimbic system and the latter the nigrostriatal

projections that are key for motor control (Wise, 2009).

4.1.2. Different receptors in different brain regions

Dopaminergic input, besides the striatum, project from the VTA to the PFC (Doya, 2002). Its

effect is mediated through five different metabotropic G protein-coupled receptors (Beaulieu &

Gainetdinov, 2011) that are differentially functional as well as differentially spread out in the brain.

The D1 and D2 receptors are significantly present in the amygdala whereas the D5 receptors are

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present in a high concentration in the pyramidal neurons of the PFC (Beaulieu & Gainetdinov, 2011).

They are all present in other regions, in addition to the other two receptors; however, it is less

significant for this paper.

Some examples for the rewarding function of dopamine will be given here since they interaction

of this system with social behaviour is obvious, even if it is not directly related to aggression or

impulsivity. Dopamine is rewarding when there is a spike in its activity and certain dopamine

receptors, such as D4, have different polymorphisms that allow levels of sensitivity and stronger or

weaker good feeling that is very important for the sort of social behaviour humans present (Bachner-

Melman et al., 2005). The prediction errors for reward, or lack thereof, have been correlated to

spikes in dopamine activity in the midbrain following unexpected reward, or alternatively, a dip

following a lack of an expected reward (Schultz, 2004, 2007, in Rogers, 2011).

Other dopamine receptors are studied in other contexts. Of relevance for our paper is the

interventions performed on the dopaminergic systems in order to reduce aggression. For instance,

haloperidol has been used for many years as a treatment for psychotic patients. Haloperidol acts as

an antagonistic agent on the dopamine D2 receptors (de Almeida et al., 2005). In other research it

has been found that D2 receptor antagonists also hinder people from detecting angry faces (Seo et

al., 2008). D2 receptors also have two isoforms that have been studied in mouse models: D2L, long

form, and D2S, the short one, and in the mouse brain the long form is more abundant, with an overall

D2 density reduction with old age (Vukhac et al., 2001). It has been observed that older mice are

significantly less aggressive, moreover, mice lacking the long isoform, D2L, are significantly less

aggressive, without losing overall D2 density (Vukhac et al., 2001). D2 receptor’s role is deeper than

aggression though since it could be characterised as working to regulate compulsions and impulsive

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behaviour as has been shown with the effects on gambling behaviour with people who take D2

affecting drugs (Rogers, 2011).

4.1.3. Parkinson’s and L-dopa

Since dopamine is produced in the substantia-nigra that is the main target of Parkinson’s

disease, a large amount of research is focused in that area. The loss of dopamine producing neurons

leads to loss of fine motor control as well as impulsive behaviour such as compulsive gambling and

binge eating (Brichta et al., 2013; Dalley & Roiser, 2012; Okai et al., 2011). The standard treatment is

using L-dopa, an in-between molecule in the process of converting tyrosine to dopamine, in drug

form (Brichta et al., 2013; Segura-Aguilar et al., 2014). Thanks to this treatment, tests can be

performed comparing patients in their “on” and “off” states. For instance, in “off” state, patients

show impatience in a delayed discounting task (Dalley & Roiser, 2012). This is implicating both L-

dopa, thus dopamine in general, as well as D2/D3 specific agonists that are also sometimes used as

drugs. The D2 receptor is also associated with learning as another Parkinson’s study shows us.

Patients in the “off” mode learnt better from negative outcomes than from positive outcomes, while

this was reversed in the “on” mode (Frank et al., 2004, in Rogers, 2011).

Further data on the D1 and D2 function in the amygdala is given by Smith, Geissler, Schallert, and

Lee (2013) using a Parkinson’s disease animal model. The study focused on a cognitive attention

switching behaviour that is also deficient in patients. The importance of the dopamine projections

from the substantia-nigra to the amygdala are stressed in this study and D1 importance in a

switching as well as a 5-CSRT task.

4.1.4. Other manipulations to dopamine

Administering L-dopa is a similar treatment to tryptophan supplementation in order to examine

higher levels of serotonin. Also specific agonists can be used in the case of the different dopamine

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receptors, as has been described for some of the Parkinson’s disease studies. Additionally, targeting

neurons using toxin injections or knockout models is used in dopamine research as it is used in 5-HT

research.

4.2. Dopamine and impulsivity

The D2 receptor is associated with impulsivity and aggression, and D1 is associated with decision-

making (Rogers, 2011). A few studies described in his review indicate an interaction taking place in

the anterior cingulate cortex (ACC) and the nucleus accumbens that seem to reflect cost-benefit

calculations. This has been surmised from rats being observed willing to exert more effort for larger

rewards. Rogers further describes the distribution of the D1 and D2 receptors as being instrumental in

the balance between the direct and the indirect striatal pathways (2011). These two pathways are

believed to dominate the Go and No-Go competing actions respectively. While there is empirical

support of this hypothesis, affirming these assumptions with humans is at the moment tricky due to

drug selectivity and location of action. D1 receptors, and not D2, are associated with fear learning as

well as with mechanisms that involve the decisions relevant for the 5-CSRT (E. S. Smith et al., 2013).

Impulsive behaviour is often observed in substance abusers. Rogers (2011) discusses the

deficiencies substance abusers have in probabilistic decision making that would be caused by

damage to the fronto-striatal systems. However, as he further remarks, it could be that the drug

seeking, impulsive, behaviour is the cause of an innate irregularity in the system that affects

decision-making.

4.3. Link between dopamine research to predator and prey behaviours

How to link dopamine effects to predator and prey behaviour becomes a bit tricky, despite the

effects it has on decision-making and the close link to the serotonin system. McEllistrem (2004)

discusses some evidence found, most of it from research that is a little dated. In cats, dopamine

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agonists reduced hissing and reduced reactive aggression while antagonists have had the opposite

effect. This is in line with evidence from clinical cases where haloperidol, a dopamine antagonist, is

used to treat violent cases. Additionally, as has been previously discussed, the D2 receptor role in

aggression and impulsivity, as well as the D1 role in fear learning, which leads to a certain expected

interaction between the two in prey reaction to a threat.

Dopamine seems to be a potentiator, through D2 receptor activation, of both predator and prey

types of aggression (Siegel & Victoroff, 2009). There are dopaminergic projections connecting the

VTA to the hypothalamus and the limbic system through which this effect takes place. Siegel and

Victoroff (2009, p. 211) also suggest that dopamine is “permissive” in aggression, rather than

initiating it. Thus in essence, the dopamine system’s interaction with other systems is how it exerts

its effect and this is what we are now going to examine.

5. Interactions between serotonin and dopamineThere are only a few studies that touch on the interaction between the serotonergic and

dopaminergic systems. For instance, these interactions between 5-HT and dopamine have been

found in rats under the influence of d-amphetamine (Dalley & Roiser, 2012). Amphetamine is a

stimulant that increases the levels of dopamine and thus is believed to reduce impulsive action in

the delay-discounting task. However, rats that have been depleted of serotonin do not experience

this improvement in decision-making (Dalley & Roiser, 2012). Rogers (2011) in his review also

suggests that serotonin and dopamine have complementary roles. In the article another evidence to

point it out is that tryptophan depletion removes the rewarding effect of cocaine in humans, while

SSRIs reinforce the effects of cocaine in rats.

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An interesting finding concerning both the PFC and the striatum and attentional control involves

a study including healthy individuals who ingest a tyrosine and/or tryptophan deficient diet in order

to cause an acute serotonin and/or dopamine deficiency (Scholes et al., 2007). In this research,

Scholes et al. (2007) found that individual decreases of these two neurotransmitters improves

attentional control as it is measured by the Stroop task (depletion of both dopamine and serotonin

was insignificant). Also this experiment indicates a close link between the two systems, in this case,

on attentional control. This is further supported by a study using 8-OHDPAT to excite 5-HT1A neurons

(Lladó-Pelfort et al., 2012). It was shown that the excitation of these neurons in the hypothalamus or

raphe nuclei does not lead to increased pyramidal neuron firing while in the medial PFC this same

agonist activates preferentially GABAergic neurons that lead to a disinhibition of pyramidal neurons

that in turn affect downstream dopaminergic neurons.

6. DiscussionWe first started with a definition of aggression. If we would ask what the purpose of aggression

is in evolutionary terms, it is “as solutions […] to a host of distinct adaptive problems, such as

resource procurement, intrasexual competition, hierarchy negotiation, and mate retention” (Buss &

Shackelford, 1997). It is difficult to place predatory aggression on this scale. As Siegel and Victoroff

(2009) question, what is the function of this type of aggression. Additionally, they point out, there is

much more research into the defensive type than the predatory one.

Definition of impulsivity in the lab is still unclear since it seems to depend on the test performed

or the questionnaire given. Dalley and Roiser (2012) present that the D2/3 antagonist eticlopride,

when it was infused into the nucleus accumbens, resulted improved performance in the 5-CSRTT. In

that same paper, they also indicate that D1/2 antagonists, systematically administered, lead to

40


increased impulsivity in delay-discounting tasks. We can question the role of the different locations

of the receptors in the brain, or across the synaptic cleft, but it would be wiser to first question the

task and ask what sort of conclusions it leads us to.

Another point of discussion is brought by de Almeida et al. (2005). In their paper they

questioned the underlying assumption that sampling of CSF at a certain instant indeed exemplifying

the regular levels rather than what it is, a single moment’s sample.

A true confounder in the data comes from Murphy et al. (2009) who investigated the reflection

effect. This effect demonstrates the misguided ideas concerning gains and losses people have. Given

the choice between a certain win, a 50/50 chance of double that amount, or no win at all, people

tend to go for the certain win. This risk-aversive choice is reversed when the same choices are given

with the option to lose a certain amount. Thus, when the option is to lose money, people are more

willing to seek more risk. This risk-seeking versus risk-aversive behaviour is modified by tryptophan

supplementation. The participants who were on an added tryptophan diet took a longer time to

reach their decisions, both for wins and even more so for losses (Murphy et al., 2009). Additionally,

they seemed to be more risk-seeking for the wins while being more risk-aversive for the losses. This

reversal is difficult to explain but perhaps could suggest that the increased levels of 5-HT allowed for

more learning and therefore the decisions made were made within a broader frame of all the losses

and wins in the experiment.

Aaldering and de Dreu's (2012) hawkish and dovish paradigm of research placed some

participants as hawks and others as doves thus artificially endowing them with character.

Interestingly, this empowerment, or pacification, indeed was reflected in their behaviour. Booij et

al.'s (2010) longitudinal study followed children with a history of aggression over 21 years and found

that following that period, even the ones with low 5-HT concentrations do not present the

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heightened levels of aggression. Both of these studies conclusions suggest together that perhaps the

most important thing is the environment and the external input, and not the anatomy or

neurotransmitters; there may be a tendency, more in some than in others, but eventually this

reflects what is imposed on it. This is in a similar vein with (De Dreu, 2012; Israel, Weisel, Ebstein, &

Bornstein, 2012) concerning the effect of oxytocin, which interacts with the serotonergic system, in

different contexts. This also follows from a line of research on the effects of chronic stress on the

alteration of monoamine levels in the brain (Roberts, 2011).

Bottom line, we shouldn’t forget that we are trying to model very complex behaviour based on

evidence from very specific brain circuits and experiments that look at them and this is never going

to be one-to-one. This entire paper attempted to draw connections post-hoc between many studies

performed on aggressiveness and impulsivity and the predator-prey situation which has only one

published study based on that paradigm (De Dreu et al., 2014). There are bound to be some

suggestions for links that should be scrutinized and executed in a specialised research. For instance:

the specific 5-HT receptors that activate in the amygdala during a fearful reaction and examine the

causation of amygdala-hypothalamus interaction. It is to be hoped that the outline given for two

differently motivated aggressive behaviours was sufficient to convince that they are indeed rooted

differently in the brain circuitry and neurotransmitter systems that dominate them. Future research

should examine the motivations for intraspecies predatory behaviour in order to better create this

construct of aggression.

Acknowledgements:

The author would like to thank Joëlle Lafeber and Simon Columbus for their feedback on writing.

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The roles of serotonin and dopamine in reactive and ...

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