MULTIPLE FACETS OF ANGER:

GETTING MAD OR


RESTORING JUSTICE?
!ii
Evolution and Schizophrenia

MULTIPLE FACETS OF ANGER:

GETTING MAD OR

RESTORING JUSTICE?

Farzaneh Pahlavan

Nova Science Publishers, Inc.

New York
!iii
Alexis Lieberman, and Joav Merrick

Copyright © 2010 by Nova Science Publishers, Inc.

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!iv
Evolution and Schizophrenia

CONTENTS

Farzaneh Pahlavan ii
Contents iv
Introduction i
Chapter 3 7
The Neurobiology of RAGE and Anger & Psychiatric Implications with a Focus on
Depression 7
!i
Introduction

INTRODUCTION

This book is an attempt to document the current state of research on anger, and to reflect
the expanding understanding of how anger as an emotion interfaces with other aspects of
psychological functioning, including behavior. It takes into account work by pioneers in this
field as well as efforts by new investigators. All have to deal with the ambiguity and
subjectivity of the construct by being clear about how they conceptualize it. These chapters
provide a representative rather than exhaustive sampling of cutting-edge research and theory
on anger.
It has been about three decades since the publication of Averill’s book which gave a new
picture of anger through its connection with cognitions (Averill, 1982). The analysis of anger
in Western thought can be traced as far as fourth-century BCE in Greece. Aristotle (384-322
B.C.) proposed the idea that anger is a rational and natural reaction to offense, and hence
closely aligned with reason. In the Rhetoric (1991, p. 1380) he defined anger as “a belief that
we, or our friends, have been unfairly slighted, which causes in us both painful feelings and a
desire or impulse for revenge.” Although, details, including assumptions about the relative
importance of conscious and unconscious influences, have varied over time, this same
division into biologically-unconscious based influences and conscious mental and behavioral
influences on anger has continued to characterize psychologists’ thought over two millennia.
At the beginning of the twentieth century, while psychoanalysts (e.g. Freud 1920) were
elaborating a psychology of the unconscious, including innate and inherently antisocial sexual
and aggressive drives that blindly seek expression and satisfaction (i.e. the id), behaviorists
(e.g. Watson, 1913) refused to say anything explicit about unconscious processes, treated
conscious experience as epiphenomena, and saw “the mind” in some way as a black box.
Hence, while the psychoanalytic approach dealt exclusively with aggression, and held that
anger was subsumed under aggression and a part of the death drive, behaviorists avoided
analyses of internal processes altogether. In vogue for many years, the Frustration-Aggression
hypothesis followed the Freudian approach in equating anger with aggression. During the
1950s and 1960s, psychologists writing about anger explained it as the mediator of the
relation between frustration and aggression. Distinguishing between the emotion of anger and
its expression in action, the frustration-aggression hypothesis (Dollard, Doob, Miller,
Mowrer, & Sears, 1939) with its extension to anger (Pastore, 1952; Berkowitz, 1962) may be
viewed as a precursor to the cognitive era. However, being primarily behavioristic, the
differentiation of anger from other negative emotions was not of specific interest for
advocates of the frustration-aggression hypothesis, nor were psychological processes related
to the regulation of anger expression. Only the development of the cognitive approach
allowed a clear cut distinction between anger and its behavioral expression (Averill, 1982).
Thus, details changed as dominant metaphors for mind changed, from a hydraulic system
at the beginning of the twentieth century (e.g. Freud, 1920), to the computer system
!ii
Farzaneh Pahlavan
(Kihlstrom, 1987) passing through the metaphors of a black box or homunculus. The
computer as metaphor enabled the conceptualization of human mind in terms of meta-
cognitions operating under the influence of complex higher-order mental processes, without
any assumption based on innate drives that seek gratification without regard to the constraints
of social reality. The development of the cognitive approach in psychology led to a range of
discoveries about the complex mental processes underlying affect, motivation, and cognition,
including anger and its concomitant perceptual, motivational, decisional, and behavioral
processes.

SO WHAT’S NEW IN THE STUDY OF ANGER?

Averill, as one of the pioneers in the field, raises ten basic questions that are implicit in
decades of research on “basic” or “controlled” processes involving anger, but seldom
confronted so explicitly and elegantly. Averill in his chapter (chapter 1) tries to convince
readers that (1) anger is not a thing in itself; (2) aggression, although a prototypic feature of
anger, is one of its less common forms of expression; (3) social beliefs and rules are principal
organizers of anger; (4) on an abstract level, anger-like emotions are universal because their
social functions are vital to any society, but, on a more specific level, each society has its own
way of fulfilling those functions; (5) the experience of anger is often a post hoc interpretation
of one’s own behavior; (6) modern men as well as women are often the victims of domestic
violence, typically attributed to anger; (7) anger can, but should not, serve as an excuse for
violence; (8) anger can sometimes facilitate recovery from disease; (9) catharsis is not a
purgation of angry feelings, but learning how to respond creatively to provocation; and,
finally, (10) anger can be conceived of as a transitional social role.
The frustration or thwarting of a goal commitment is still basically and historically
understood as a factor which can lead to various negative emotions, such as anxiety, shame,
guilt, and of course anger, potentially in dynamically significant patterns. Recent conceptions
of aggression, traditionally thought of as a behavioral expression of anger, paint a more
complex picture of the link between the two. Berkowitz (chapter 2) note how complex the
“anger-aggression” relationship has become since his first related proposition (Berkowitz,
1962), and modifies this picture even further. Berkowitz defines the anger experience as
largely the sensations of an activated aggression-related motor program and its associated
neural/bodily changes, along with whatever primed ideas come to mind about the instigating
situation. He presents these neural/somatic/cognitive activities as automatic responses to two
kinds of factors: (a) the intense, active negative affect produced by decidedly aversive
occurrences, and/or (b) stimuli (either internal or external) that are associated with decidedly
negative happenings and/or with aggression generally. When intense enough, aggression-
related reactions will be manifested in an impulsive attack on an available target,
independently of cognitive mediation, although appraisals and other high order cognitions can
come into play somewhat later and essentially as an afterthought, in order to guide an
individual’s actions. Berkowitz supports his arguments with evidence from a series of studies
conducted in different fields. As a concluding thought, he argues that whatever else an angry
person may want to do, they want to hurt someone ─ the perceived source of their strong
displeasure, and perhaps also those associated with this source.
New investigations of anger are thus more concerned with the modulation of the
relationship between frustration, anger and aggression by subjective interpretation of the
threat or frustration as an assault on one’s personal or social identity. In addition to the causes
of the experience of anger, goals, motivation, and self-regulation are prominent in the new
conceptualization of anger. Understanding how and when anger arises requires many levels of
!iii
Introduction
analysis. The tools and findings of neuroscience have much to contribute to this effort.
However, it is practically impossible to summarize the contributions of any field of
psychology, specifically neuroscience, to new understandings of anger, given the rapid
developments and extensions in this field. Guerra, Colonnello, and Panksepp (chapter 3)
illustrate the kind of complex interactions that are likely to exist in many domains in regard to
anger, by focusing on the biological roots of impulsive aggression that arises from humans’
genetically endowed capacity for anger, and the affective state that the authors attributed to
what they call the RAGE circuitry of the brain. The authors advocate the idea that at its most
fundamental level RAGE is a primary-process emotion, and is aroused by certain types of
irritation and restriction of freedom. However, in order to offer a complete vision of the
neurobiology of emotion, they also discuss secondary processes, related to basic mechanisms
of emotional learning, as well as tertiary-processes emotions, related to our capacity for
cognitive reflection and thought, as important issues that remain to be well-studied at the
neural level. For these authors, anger can be characterized as a long-term behavior with
episodic presentation, which requires programming, memory, and the continued
reinforcement of specific neuronal circuitry. The authors suggest that dynamic systems
approaches (Panksepp, 2000), which incorporate an emerging theory that combines
neurogenesis, neural ontogeny, neurotransmitter and hormonal development as well as the
environmental (re)-programming of gene expression (epigenetics, chromatin remodeling),
may help understand the biological psychology of RAGE and other emotions. However, for
the authors, this dynamic systems approach in no way diminishes the importance of early
childhood rearing, personal emotion regulation, and intelligence in moderating biological
dispositions to behave in anti-social ways, making clear that exchanges with social
neuroscientists, social psychologists, and developmental psychologists may be highly fruitful.
In the same vein, von Salisch and Saarni (chapter 4) consider the family as a key to the
development of anger related processes, and examine the roots and sequences in development
of these processes. In their chapter, focused on development and function of anger in
childhood, von Salisch and Saarni trace stages in the development of anger and show how
anger develops in complexity and scope across the age periods of infancy (0-1 year), early
childhood (1 to 5 years), middle childhood (6 to 10 years), and preadolescence to late
adolescence (11 to 19 years). Their analyses are guided by their theoretical position, leaning
toward a social constructivist platform: Children and youth actively construct their experience
of anger in their social relationships, for example by labeling situations as anger-provoking or
their bodily sensations as anger. Thus, von Salisch and Saarni argue that cognitive
development plays a significant role in these constructions and in the development of other
aspects of anger as well. In their discussion of appraisal processes, they suggest that the
appraisals involved in the elicitation of anger change with development, leading to individual
differences in coping with anger, including differences in terms of gender, culture or
temperament (or personality style).
Given the wide spread of both awareness and strong opinions about affective
vulnerability induced by negative affective states, including anger, Forgas (chapter 5)
proposes to take a look at another side of the coin, and examine whether negative affective
states can sometimes be seen as useful and even essential components of adaptive responding
to social situations. For him, affect is an integral aspect of social thinking and behavior, and
as such plays a crucial role in how people organize and represent their social experiences.
Trying to provide some insights regarding the relationship between the rational, cognitive,
and emotional affective faculties of human beings, he describes a number of original
experiments showing that negative affective states can produce surprising and unexpected
benefits, such as improving memory, reducing errors of judgment, and promoting more
effective social behaviors. In contrast with the overwhelming emphasis on the benefits of
!iv
Farzaneh Pahlavan
positive affect, Forgas provides evidence that highlights the potentially adaptive and
beneficial consequences of negative mood. Because dealing with social information is
necessarily a complex task requiring a high degree of elaborate processing, Forgas (1995)
argues that in many situations, negative affect such as sadness may increase, and positive
affect decrease the quality and efficacy of cognitive processes and interpersonal behaviours.
Similarly, Wranik (chapter 6) presents an updated and critical review of research on
causes and consequences of anger in the workplace. She finds, surprisingly, that anger can
lead not only to negative results but also to a whole range of positive processes and outcomes.
After defining emotions and explaining why individuals have anger at work, she examines
how anger can be both a positive and a negative emotion. In the final section, she tries to
uncover how emotional competencies can influence how anger is effectively used and
managed at work. In her conclusion, she argues that anger does not emerge from specific
situations or from general environmental or biological factors, but from the way that
individuals subjectively evaluate situations or events. Moreover, and contrary to the popular
conception of anger as destructive or harmful, she argues that anger has many useful
functions. Because experiencing anger is normal and tends to signals one’s need or desire for
change, individuals can learn to harness the emotion for their own needs and goals.
Nonetheless, the way that individuals express their anger, or how they behave in any given
situation, can be developed and learned, so that the need for change can be expressed as
constructively and realistically as possible. Given that anger is one of the most frequent
emotions in the workplace, for Wranik it might make sense to learn as much as possible about
this complex and important emotion.
Indeed, anger is one of the most frequent emotions experienced everywhere (Averill,
1982): its analysis must, therefore, take into account the contextual complexity of its
expression. Given that anger has the potential to seize a group of individuals, or even a
nation, and persist from as little as a few minutes to a much more sustained period (Lerner,
Gonzalez, Small, & Fischhoff, 2003), it is important to understand its effects on judgment and
decision-making over time. Pahlavan (chapter 7) reviews research on anger, and examines the
ways in which recent theoretical developments make it possible to analyze the uniqueness of
its effects on judgment and decision-making processes, as the principal emotion associated
with justice judgments. She reports some of the growing body of empirical studies that
address anger’s relation to self-control processes understood in terms of High- vs. Low-level
construals of information about self, others, and values as a function of their psychological
distance. She also tries to outline and describe what is known about functional shifts in mind
set induced by threats to social values. The research reviewed in her chapter outlines a general
theoretical framework integrating findings from the literatures on Construal Level Theory
(Trope & Liberman, 2003) and Social Functionalism (Tetlock, 2002). On one hand, Construal
Level Theory proposes that any factor that systematically changes levels of construal, such as
psychological distance from the events, may affect individuals’ self-control processes. On the
other hand, Social Functionalism suggests that any perceived threat to bedrock social values
may shift individuals’ mind-sets from cold intuitive scientists or economists to angry intuitive
prosecutors or theologians. She makes the case that regulation of anger-inducing situations
may lead to shifts in mind set through the activation of high-level construals. Her chapter
ends with a discussion on how application of this integrative reflection may offer some
insight into the processes underlying moral disengagement (Bandura, 1999).
As a basic emotion, anger emerges early in life and has a unique adaptive function in
motivating, organizing, and regulating behavior. No other emotion can match the consistency
and vigor of anger in mobilizing high-level energy and sustaining goal-directed activity.
Anger serves a variety of regulatory functions in physiological and psychological processes
related to self-defense as well as to interpersonal and societal behaviors. Through
!v
Introduction
socialization processes, it plays an important role in the development of personality and
individual differences in responding to environmental challenges, which can be more or less
adaptive. So, while everybody may feel flushed, uncomfortable, and want to start a fight, it is
also true that without any thwarting of a goal, an awareness of an offense or the threat of this,
those feelings would not count or be felt as anger. Having a goal commitment thwarted by a
perceived social context increases the probability of feelings of anger. Nevertheless, these
processes vary in importance among individuals, but also among groups of individuals who
share a common social culture and structure wherein they learn its “display rules.” Societies
treating some goals and values as desirable help to determine when, to whom, and how to
express anger. In other words, in spite of considerable individual variation in the organization
of goals within a given society, common goals and values also have shared influences on
feeling and expression of anger, specifically those related to one’s self- or social identity.
Failure to fulfill such a goal contributes to great emotional vulnerability, and behavioral
disorders. Thus, there is no direct and unique relation of anger to aggressive behavior or any
other destructive behavior. Anger leads to many other forms of behavior, and its expression
may even prevent aggression.
The contributions in this volume identify many of the factors and processes involved in
the experience, expression, and control of anger. A wide variety of factors, processes, and
their interactions are considered. Nevertheless, as with other topics related to human nature,
our understanding of anger-related processes is partial, but has the potential to develop. Some
of its features have the potential to change our understanding of our social institutions and
challenge “common sense” views. Nevertheless, important issues remain to be fully
articulated. It is not clear, for example, how the experience of anger—which influences our
reactive capacity for cognitive reflection and thought, in terms of self/group beliefs, blaming,
and accountability—impacts or is affected by culture and institutions. By examining the many
factors and processes involved in these interactions, this volume contributes to a further
understanding of why, how, and when the expression of anger is beneficial or harmful. The
complexity involved is humbling, but not in any way discouraging. It only means that there is
still plenty of research to do.

REFERENCES
Aristotle (350 BCE/1991). Rhetoric (H. Lawson-Tancred, Trans.). New York: Oxford
University Press.
Averill, J. R. (1982). Anger and aggression: An essay on emotion. New York: Springer-
Verlag.
Bandura, A. (1999). Moral disengagement in the perpetration of inhumanities. Personality
and Social Psychology Review, 3, 193-209.
Freud, S. (1920). A general introduction to psychoanalysis. New York, NY, US: Horace
Liveright.
Watson, J. B. (1913). Psychology as the behaviorist views it. Psychological Review, 20, 158–
177.
Kihlstrom, J.F. (1987). The cognitive unconscious. Science, 237(4821), pp. 1445-1452.
Dollard, J., Miller, N.E., Doob, L.W., Mowrer, O. H., & Sears, R.R. (1939). Frustration
and aggression. New Haven, CT, US: Yale University Press.
Berkowitz, L. (1962). Aggression: A social psychological analysis. New York, NY, US:
McGraw-Hill.
Pastore, N. (1952). The role of arbitrariness in the frustration-aggression hypothesis. The
Journal of Abnormal and Social Psychology, 47(3), pp. 728-731.
!vi
Farzaneh Pahlavan
Panksepp, J. (2000). The neurodynamics of emotions: An evolutionary-neurodevelopmental
view. In Emotion, development, and self-organization: Dynamic systems approaches to
emotional development. M.D. Lewis & I., Granic (Eds.); New York, NY, US: Cambridge
University Press, pp. 236-264.
Forgas, J.P. (1995). Mood and judgment: The affect infusion model (AIM).Psychological
Bulletin, 117(1), 39-66.
Lerner, J. S., Gonzalez, R. M., Small, D. A., & Fischhoff, B. (2003). Effects of fear and anger
on perceived risks of terrorism: A national field experiment. Psychological Science,
14(2), 144-150.
Tetlock, P.E. (2002). Social Functionalist Frameworks for Judgment and Choice: Intuitive
Politicians, Theologians, and Prosecutors. Psychological Review,109 (3), 451–471.
Trope, Y., & Liberman, N. (2003). Temporal construal. Psychological Review, 110, 403–421.
 Chapter 3

THE NEUROBIOLOGY OF RAGE AND ANGER &

PSYCHIATRIC IMPLICATIONS WITH A

FOCUS ON DEPRESSION

Daniel J. Guerra1*, Valentina Colonnello2 and Jaak Panksepp3+

1 Department of VCAPP, College of Veterinary Medicine,Washington State
University, Pullman, Washington USA
2 Department of VCAPP, College of Veterinary Medicine,Washington State

University, Pullman, Washington USA

3 Baily Endowed Chair of Animal Well-Being Science

Department of VCAPP, College of Veterinary Medicine, Washington State

University,
PO Box 646520, Pullman WA 99164-6520, USA

Anybody can become angry, that is easy; but to be angry with the right person, and to the
right degree, and at the right time, and for the right purpose, and in the right way, that is not
within everybody's power; that is not easy.

Aristotle (~320 BC)

“Irascimini, et nolite peccare” ("Be angry and sin not")

Old Testament (Fourth of Psalms)

* Email: djguerra@wsu.edu

+ Email: jpanksepp@vetmed.wsu.edu
!8
Daniel J. Guerra, Valentina Colonnello and Jaak Panksepp
ABSTRACT
There has been a perennial debate about whether aggression is learned or innate. The
power of extreme arguments in this area has diminished as all are beginning to recognize
that both evolution and learning contribute much to our tendency to be aggressive in
various distinct ways, including impulsive anger, premeditated predatory behavior in its
many forms, as well as our seeking of dominance as exemplified best in inter-male
jousting. Here we will be almost exclusively concerned with the biological roots of the
type of impulsive aggression that arises from our genetically prescribed capacity for
anger, and affective state that we label the RAGE circuitry of the brain.

INTRODUCTION
There has been a perennial debate about whether aggression is learned or innate. The
power of extreme arguments in this area has diminished as all are beginning to recognize that
both evolution and learning contribute much to our tendency to be aggressive in various
distinct ways, including impulsive anger, premeditated predatory behavior in its many forms,
as well as our seeking of dominance as exemplified best in inter-male jousting. Here we will
be almost exclusively concerned with the biological roots of the type of impulsive aggression
that arises from our genetically prescribed capacity for anger, and affective state that we label
the RAGE circuitry of the brain.
At its most fundamental level RAGE is a primary-process emotion that is aroused by
certain types of irritation and restriction of freedom. Please note, that we capitalize emotional
terms when we refer to the various distinct functional networks for emotionality that are built
into the brain neurobiologically as ancient forms of mentation that preceded higher mental
processes (as noted in the above epigrams) by eons of evolutionary time. Ancient subcortical
brain circuits generate various ancient mental energies (emotional feelings or affects) we will
discuss in this essay, even though we will not neglect secondary-processes related to basic
mechanisms of emotional learning as well as tertiary-processes emotions related to our
capacity for cognitive reflection and thought (highlighted in the epigraphs noted above),
important issues that remain to be well studied at a neural level (Pahlavan, 2004). In the
human BrainMind, all these levels of control inextricably interact, and the primary-process
issues can only really be dissected with animal brain research (e.g., Panksepp, 1971, 1998).
Here we will not focus as heavily on the possible cognitive subtleties of aggression as in
a recent previous review (Panksepp & Zellner, 2004), but focus more heavily on the
neurochemical underpinnings. We would simply note that with ever more neuro-evolutionary,
higher-cerebral capacity for cognitive activity, when desired rewards are not forthcoming,
transitions from frustration to free-floating irritability and directed anger may erupt. In the
intact developing organism we will most commonly use the conflated term RAGE-anger,
since one cannot yet monitor their cognitive activities, even though affective state can be
monitored by determining whether artificial arousal (e.g., electrical or chemical stimulation)
of emotion-mediating neural circuits can serve as rewards or punishments (Panksepp, 2005).
Thus in a primal RAGE-anger state, muscles tense up, respiration accelerates, heart beats
faster, and blood pressure increases. Animals escape such brain stimulation if given the
chance (Panksepp, 1971). Attention is completely absorbed by irritating stimuli, while the
whole body becomes promptly ready to confront and overcome the perceived source of anger.
RAGE-anger has been part of the human experience throughout evolution and this affect has
likely arisen from lower vertebrates through primates via limbic structures well established as
mediators of primary-process anger-related behaviors that are the sources of primal RAGE
!9
Neurobiology of RAGE and Anger
(Panksepp, 1998; Siegel, 2005). In humans, anger emerges in early infancy: children 4-7
months old are able to both recognize (Serrano et al., 1992) and clearly display signs of anger
when abruptly deprived of expected pleasurable stimuli, and, even at 2 months of age, when
obstructed in pursuing an activity (Alessandri et al., 1990; Lewis et al., 1990; 2006). Even if
the ontogenesis of anger responses seems to emerge after the cause-effect relation is learned,
young children who are not yet able to conceptualize the source of irritating stimuli still
display RAGE responses when experiencing a physical restraint (Sullivan and Lewis, 2003;
Moscardino and Axia, 2005). To the best of our knowledge, arousal of this emotion is largely
characterized by negative affect (Panksepp, 1971).
Anger appears early in child development and is widely considered a preserved
evolutionary adaptive response that enables the organism to enhance the probability of
reaching the craved resources by vigorously attacking perceived frustrating stimuli (Darwin,
1965). During the interplay between infant temperamental traits and certain early social
environments, anger may become one of the predominant responses to external stimuli and
the RAGE outburst a recurrent response. This is especially evident in children with
ambivalent-resistant attachment styles, where chronic frustration for the inaccessibility of the
desired resource, i.e. the attachment figure, is consistently expressed by anger responses
(Bowlby, 1973; Main and Morgan, 1996). This attachment style is associated with later
childhood aggression (Kokko et al., 2009). A sustained anger state potentially becomes a
stable irritable personality trait carried over in various contexts, primarily in social
relationships. Anger is common also in early emergence of mood disorders, as evidenced in a
study on preschool children, where Levi et al. identified anger, as one of three dominant
affects in early patterns of depressive disorders (Levi et al., 2001), indicating that the
emergence of subtypes of depression can be detectable also in early childhood.
The manifestation of pathological anger and aggression in early age may persist in
adolescence and in later stages of life and permeate the developmental pathway (Cummings
et al., 1989; Keenan et al., 1998; Calkins and Fox, 2002). An extensive literature converges in
indicating a high comorbidity between aggressive behavior and depression both in children
and adolescents, with the prevalence of these disorders increasing during adolescence (Wolff
and Ollendick, 2006). In this instance, a longitudinal study focused on the developmental
trajectories in bullies and bully-victims documents that not just children victims of peer-
aggression, i.e., the bully-victims, but also boys who were bullies at 8 years old reported
symptoms of severe depression ten years later (Kolmek et al., 2008). The later depression
may be the outcome of a lack of social adaptation due to a difficulty in elaborating the
feelings of anger and regulating its expression (Cole et al, 1998).
Moreover, in adult psychiatry, the outburst of anger attacks is considered among the
criteria for the diagnosis of several psychiatric syndromes. In particular, its presence appears
as criterion for several manifestations of depression and for bipolar disorder with manic
episodes; also, the degree of anger is correlated with the severity of depressive symptoms
(DSM, American Psychiatric Association, 2000; Dougherty, et al 2004). As mentioned, the
depressive disorder is not a homogenous phenomenon, and the subtype of depression
associated with anger may emerge early in the development. The relationship between anger
and depression received particular attention also in adult psychopathology. Already Freud
hypothesized that the depressive mood is the results of aggressiveness turned inward (Freud,
1917), which finds its clear expression in suicide attempts. In support of the anger turned-in
hypothesis, several recent studies demonstrated that depressed subjects with anger attacks
showed more suicide predisposition compared to depressed patients without anger attacks
(Conner et al., 2003; Painuly et al., 2007). On the other hand, more recently it has recognized
that also in adults the relationship between aggressiveness and depression is more complex
than previously hypothesized. Thus, both in children and in adult psychopathology, it has
!10
Daniel J. Guerra, Valentina Colonnello and Jaak Panksepp
been suggested that specific subtypes of depression may be differentiated considering the
underlying dominant distinct basic affects, i.e., anger/RAGE, FEAR, and sadness/PANIC
(Levi, 2001; Lara, 2006; Panksepp, 2006). In addition to depressive disorders, outburst of
anger is considered in the diagnosis of PTSD, Generalized Anxiety Disorder, Borderline,
Antisocial, and Paranoid personality disorders. Thus, it is clear that the anger manifestations
are evident in several psychiatric syndromes.
However, a diagnostic category of anger disorder per se has not been contemplated in
either the DSM-IV-TR or ICD-10, and even if it is one of the criteria, anger is often
considered as a secondary aspect of various psychiatric syndromes. In short, the presence of
excessive anger is not regarded as the main criterion for the diagnosis of any of the
abovementioned disorders (Miczek et al., 1995; DiGiuseppe and Tafrate, 2006). The only
disorder identified in the DSM-IV that apparently is closer to RAGE expression disorder is
the intermittent explosive disorder, but this diagnostic category is not inclusive of a more
stable RAGE-like phenotype and is rarer than the other anger expressions (Lachmund et al.,
2005).
The time is ripe for a possible transition from a classic nosology and relative diagnosis of
psychiatric syndromes, based on mere description and classification of symptoms, to a
clinical observation and assessment including the manifestation of basic emotional systems
and their organization and precipitation in psychopathology--namely a focus on brain
emotional endophenotypes in psychiatry (Panksepp, 2004, 2006). It is well established that
mammalian brains share several basic emotional systems and relative distinct subcortical
neural circuits: RAGE, SEEKING, FEAR, LUST, parental CARE, PANIC, and PLAY,
already extensively described (Panksepp, 1998, 2005).
Research studies on psychotherapeutic approaches indicate that treatments often lead to
more rapid breakthroughs when therapists have successfully identified clients’ underlying
dominant affects (Bridges, 2006; Burum and Goldfried, 2007; Luutonen, 2007). Recognizing
the patient’s emotional balance would enhance the possibility to formulate diagnoses and
elaborate an effective, individualized treatment for psychiatric disturbance. This approach
may shed light on heterogeneous conditions where anger is one of the main components, such
as in depression (Lara et al., 2006). The advances in the field of neuroscience encourage and
support this approach to the psychopathology. In this framework, the affective neuroscience
offers a new view to conceptualize the psychiatric disorders, encouraging an approach based
on the study of predominant affects. To this end, research using animal models has been
particularly suitable because humans share with lower animals common primary processes
affect generating emotional ssytems. Thus, to understand anger and to conceptualize this
common emotional state and its manifestation in several disorders, it is fundamental to
consider the underlying brain processes that energize and underpin daily responses to
environmental stimuli.

TYPES OF AGGRESSION
In the attempts to categorize anger and its manifestations in aggressive behavior, several
forms of aggression have been described in animal work: predatory-aggression, which finds
its expression in hunting for food; within-species aggression, expressed in social dominance;
and the affective aggression, described also as defensive-reactive RAGE response.
These different kinds of aggression and anger-related responses are subordinated to
specific emotional systems around which these manifestations are orbiting. Among these, the
RAGE system is a core mechanism for generating anger in humans as well as in other
mammals, and the defensive rage response is the manifestation of this system. In humans, the
!11
Neurobiology of RAGE and Anger
defensive rage finds its equivalent in the so called reactive aggression, which is characterized
by defensive attack responses to others’ behavior perceived as threatening ones welfare,
survival or quality of life. On the other hand, the predatory aggression- resembling the
instrumental or proactive aggression in humans- follows different brain pathways from the
defensive-rage response (Crowe and Blair, 2008).
It is certainly energized by the SEEKING system, which is responsible for mediating our
curiosity, expectancy and desires (Panksepp, 1971; 1998) but also the acting out of every type
of emotion, as for instance the seeking of safety when the FEAR system is aroused..
In contrast, no specific brain circuit has been detected so far for social dominance, which
with its inter-male aggression manifestation seems the product of the intermixture of more
systems, such as the SEEKING, RAGE, FEAR and PLAY systems. It should be noted that
each emotional system works in concert with other emotional systems and secondary and
tertiary processes, as will be discussed later.
In the present chapter, we will describe the neuroanatomical and neurochemical circuitry
involved in RAGE/anger expression, the genetic linkage with the anger trait, and the
interaction of the RAGE system with other basic emotional systems. Attention will be
specifically focused on the defensive anger response, with an additional brief account for
predatory aggression. The connections between the immune-system responses and
manifestation of anger will be then described.

BASIC NEUROANATOMY CIRCUITRY OF RAGE

Rage emerges when specific environmental stimuli arouse the neural circuitry of the
RAGE system. Even if the anger-thoughts and the related expression are modulated and
regulated by higher cortico-cognitive areas, the human basic circuitry of anger is still
subcortical. Since the early description of rage in decorticated cats (Dusser De Barenne,
1920) and dogs (Rothmann, 1923) and their responses to inoffensive stimuli, it was clear that
the rage expression is i) dependent on subcortical areas, i.e. the ancient regions play a crucial
role more than the higher neocortical regions; ii) independent of an intact cortex. It is
noteworthy that in animal models anger and aggression are difficult to separate, so in animal
models the RAGE expression has been studied observing aggressive responses.
As evidenced by the first studies based on selective ablations of brain regions and
localized electrical stimulation, the medial amygdaloid areas through the stria terminalis to
the medial hypothalamus, and specific areas within the Periaqueductal Gray (PAG) of the
midbrain compose an hierarchically organized RAGE circuit. Arousal of this system promotes
anger in all species tested. Further, these limbic structures, receive inputs from
monoaminergic fibers (see below) and sensory systems, which send direct and indirect
projections to all levels of this executive generator of affective anger-related attack.
!12
Daniel J. Guerra, Valentina Colonnello and Jaak Panksepp

!
Reprinted from Panksepp, 1998, with permission of Oxford University Press.

Figure 1. Hierarchical control of RAGE in the brain. Lesions of higher areas do not diminish responses
from lower brain regions, while damage of lower areas severedl impairs the affective attack from
stimulation of higher areas.

Among the higher limbic regions of this network, the medial nucleus, the basal complex,
and central and lateral nuclei of the amygdala play a key role in the modulation of RAGE. As
demonstrated by the stimulation of amygdaloid nucleus and the medial hypothalamus or PAG,
the first two regions facilitate the defensive rage, while the central and lateral nuclei which
mediate FEAR are involved in the suppression of RAGE behavior. Studies based on the
induction of chronic seizures in specific sites revealed that the threshold for eliciting RAGE
responses can be modulated, with seizures from the lateral and central nucleus elevating the
response threshold, while seizures of the medial sites and basal amygdaloid complex lowering
that threshold. Notably, these seizures had opposite effects on predatory aggression (Siegel,
2005) again affirming the anatomical a functional distinction between these two primal forms
of aggression.
A series of lesion studies conducted in animals during the first half of the 20th century
had already demonstrated the importance of the hypothalamus in the RAGE circuitry. Several
studies using animal models, from cats (Bard, 1934) to monkeys (Ranson, 1939) and dogs
(Rothmann, 1923), showed that a lesion of the posterior hypothalamus impairs the expression
of RAGE. Animals lesioned in this area were, in fact, not able to show any aggressive
response, even in the presence of noxious stimuli, but many other motivated behaviors were
diminished, and now it is known that these brain regions are a major corridor for a series of
pathways (including acetylcholine, dopamine, norepinephrine and serotonin) that control
sleep-waking and overall psychomotor arousal. On the other hand, additional studies
identified the anterior medial hypothalamus and related projections to the PAG as a crucial
specific pathway for defensive RAGE manifestation. It is important to consider, in fact, that
!13
Neurobiology of RAGE and Anger
the anterior medial hypothalamus receives inputs from limbic areas and sends inputs to the
dorsolateral aspect of the PAG. In studies on cats, Fuchs and colleagues performed lesions at
the anterior medial hypothalamus and then assessed the threshold for rage-like responses
following the stimulation of the ventromedial nucleus. The results identified in the anterior
hypothalamus a key area for the expression of RAGE: a lesion of this zone impaired the
expression of aggression (Fuchs et al., 1985). The importance of the hypothalamus in
modulating anger has been confirmed also in several human clinical cases, where brain
tumors stimulate a RAGE response associated to this region (Reeves and Plum, 1969).
Another fundamental area in the RAGE circuit is the PAG, which integrates the
information by virtue of its connections with several sites of the brain.
Different sources of stimuli can provoke anger, even a simple skin irritation or painful
stimulation. These pain-related senses converge in the orbitofrontal and insular cortices, and
the information is sent to the PAG. We can experience anger also when we anticipate positive
outcomes, but the actual circumstances fail to meet our expectations fully. In these situations,
our frustration is processed by reward-relevant dopamine regulated neurons of the medial area
of the frontal cortex, which then back-project to the PAG.
The overall aggressive behavior seems to emerge from a “fight or flight” response, where
a fast recognition of surrounding stimuli when facing a danger is crucial for a potential switch
from FEAR-related escaping to a defensive RAGE response. Therefore, the lateral area of the
frontal eye fields, promptly gathering and elaborating environmental stimuli, sends inputs to
the PAG as well. Also, stressful situations are accompanied by increased heart rate and rising
blood pressure along with other autonomic changes that support efficient expression of the
emotional reactions. These autonomic indexes are back-transmitted to the PAG from the
nucleus of the solitary tract, modulating the intensity of anger-aggression. The degree of
arousal and processing of sensory stimuli and control on all the behaviors is also probably
regulated through the ascending inputs that PAG receives from the amine cell groups, e.g.
locus coeruleus and raphe, which also control the quality of associated higher cortical
processing. When the bodily orientation is compromised during a full expression of rage
status, the vestibular complex sends inputs to the PAG. As mentioned above, important inputs
come from the medial hypothalamus directly to the dorsolateral area of the PAG, which may
help intensify aggression when animals are in various bodily need states (e.g., hunger or
sexual arousal).
In sum, the expression of RAGE is the result of the orchestration of different areas. The
subcortical neural circuitry that is involved in defensive RAGE is inborn and is hierarchically
organized: the responses from the highest areas are critically dependent on the lower areas. In
this instance, lesions of both hypothalamic and PAG areas decrease the responses evoked
from the amygdala. Moreover, the responses elicited from the hypothalamus are dependent on
the PAG but not on the amygdala (Figure 1, Panksepp, 1998; Gregg and Siegel, 2001).
Defensive RAGE is accompanied by unpleasant physiological arousal and negative
affects: the electrical stimulation of RAGE circuit induces escaping behavior in animals,
which promptly learn to interrupt that stimulation. On the contrary, the stimulation of the area
associated with expression of predatory attack is associated with positive affect and seems
rewarding (Panksepp, 1971). This may have implications for psychiatric disorders such as
depression, where anger is often a prominent component. Thus, it is not surprising that in
humans reactive, but not instrumental aggression, is accompanied with an increased feeling of
sadness (Raine et al., 2006), and presents high comorbidity with depressive disorder (Conner
et al., 2003; Morrow et al., 2006).
The circuitry for the predatory aggression involves the lateral hypothalamus with caudal
projection through the ventral tegmental area and midbrain PAG. Also, the ventral aspect of
the midbrain PAG seems to contribute to the positive expression of predatory attack (Siegel,
!14
Daniel J. Guerra, Valentina Colonnello and Jaak Panksepp
2005). The recognition that predatory aggression is one species-typical manifestation of the
rewarding SEEKING urge (Panksepp, 1971). In other words all the manipulations that
modulate the rewarding effects of the SEEKING system modify quiet-biting attack (predatory
aggression) in the same way (Panksepp, 1998).
As mentioned above, defensive/offensive RAGE and predatory aggression (species-
typical SEEKING) emerge from distinct systems within the brain, although they have close
anatomical proximity and connections, which seem mutually inhibitory. A natural
predisposition for an organization of the emotional systems with a balance in favor of specific
systems could explain temperamental differences and related styles in approaching the
environmental stimuli (Davis, et al., 2003). This hypothesis is corroborated also by studies on
infants showing that attention shifting is negatively associated with anger-like reactions to
frustrating stimuli (Johnson et al., 1991), suggesting the existence of inhibition between
SEEKING and RAGE systems. Babies show a basic predisposition for either SEEKING of
sources for distraction, or for a more RAGE-like response, with prevailing attention on source
of anger. Thus, five-six-month-old babies that were more inclined to look away from the
source of irritation in search of new stimuli showed less negative affects. As shown by
Crockenberg et al. (2008) the degree of infant distress and attention to negative stimuli
predicted also aggressive behavior in 2.5 year old girls, presumably related also to the social
learning process.
The attention shifting can be mediated and regulated by higher cognitive areas. As
individuals voluntarily attend to various other external stimuli, they can more easily shift their
attention away from sources of frustration. Conversely, the recall of negative events and
rumination on relative anger-triggering events are associated with enhanced anger and a
sustained arousal of RAGE system (Rusting & Nolen-Hoeksema, 1998; Denson et al., 2009).
In daily life, a way to represent this phenomenon would be to consider when our RAGE
system is already aroused, it is not easy to inhibit it and appreciate other stimuli other than the
source of frustration. However, presumably because of the connection between the two
systems and with potential regulation from higher cognitive areas, it is our prerogative to
“exploit’ the SEEKING system to imagine vivid scenarios and develop expectancies that can
mitigate our RAGE (as poignantly highlighted in the two epigrams to this chapter).
As mentioned above, the areas involved in the modulation and inhibition of anger are
neocortical, and lesions in the frontal cortical area lower the threshold for irritability (Blair,
2004). On the other hand, these lesions also reduce the duration of these responses,
highlighting the role of neocortical areas in regulating and sustaining the anger expression
(Panksepp, 1998). In this direction, a body of evidence has emerged indicating a correlation
between frontal cortical responsivity and trait anger regulation, as reported in functional MRI
(fMRI) studies (Coccaro et al., 2007; Lotze et al., 2007). Concurring with these findings,
studies employing positron emission tomography (PET) indicated that reduced glucose
metabolism in the orbital prefrontal cortex is associated with high scores reported in the Life
History of Aggression interview. This area, indeed, is rich in serotonergic innervation (see
below), which plays a key role in the regulation of and expression of RAGE-related behavior
(Panksepp, et al., 1973; Parsey et al., 2002; Siever, 2008). Notably, a lower prefrontal
activation is associated with reactive aggression, but not with instrumental aggression (Raine
et al., 1998). A low prefrontal cortex activity has been reported also among depressed
individuals with high anger and hostility traits (Dougherty et al., 2004), which as already
noted, is positively associated with reactive aggression. Thus, higher areas presumably are
involved in refinements of angry actions and feelings elaborated within the PAG. Even
though the expression of RAGE is dependent on those lower regions, the higher areas provide
regulation of those more ancient circuits. The frontal cortex plays a special role in elaborating
and interpreting environmental stimuli for changes in reward contingencies and expectancies,
!15
Neurobiology of RAGE and Anger
and with the support of the underlying SEEKING system elaborates higher (tertiary-process,
thoughtful) representation of possible outcomes. If anticipated positive outcomes do not
arrive, the underlying RAGE system are aroused, but still allowing for possible fast switches
between intense RAGE arousal and the return to SEEKING urges. In considering such
interactions, it is important to consider that dopamine can arouse both systems, and that
dopamine is merely permissive in generating the SEEKING urge.

NEUROCHEMISTRY OF RAGE-ANGER
Although there remains a great deal to be learned about the environmental and genetic
parameters of RAGE, many of the basic neurochemistries of the RAGE response have been
mapped out by pharmacological and more recently by gene-targeting approaches. The future
of pharmacological treatments for pathological anger must rely on an understanding of the
underlying brain neurochemistries. We will first present an overview of the findings of
numerous studies that have elucidated the role of biogenic amines epinephrine,
norepinephrine, dopamine, and serotonin in the regulation of RAGE-related behaviors and
feelings before proceeding to a discussion of steroids and neuropeptides, which have also
been implicated in the exacerbation and reduction of anger. The sites of action of these
molecules are widespread in the brain, including regions implicated in the regulation and
manifestation of the RAGE response described above. The implications for psychiatric
disorders such as depression are extensive.
Anger has been linked to both major depressive and bipolar disorder (Dougherty, et al
2004). To the extent that depression has been linked to chronic pain and inflammation, anger
and RAGE are important outcomes in this system and may be treated via similar
pharmacological and psychological therapies ( e.g. Everson-Rose and Lewis 2005). Anger-
associated depression and its relationship to chronic metabolic disorders including heart
disease and diabetes mellitus, can present as a co-morbid pathology in humans (Booth-
Kewley and Friedman, 1987; Levy 2002). Indeed, individuals with major depressive disorder
(MDD) and anger are particularly vulnerable to severe medical outcomes. The societal costs
of anger and RAGE in psychiatric illness relate to their contribution to violent behavior
including murder and suicide.

THE MONOAMINE CONNECTION

Early studies focused on the possible involvement of catecholamines in facilitation of
RAGE-related behaviors. Indeed, epinephrine, norepinephrine and dopamine, the most
abundant catecholamines, play important roles in energy balance, thermoregulation,
cardiovascular tone, and the general stress response, and therefore, their possible involvement
in RAGE-like responses has naturally also been investigated. Much of this work was
conducted decades of ago; for a very thorough review of that work, see Miczek (1987). Here
we will only sample key findings.
Since the 1950s, a general association between a reduction of brain catecholamine
activity and decrease of aggressiveness was found by observing patients treated with high
doses of antipsychotic drugs, such as the chlorpromazine, which reduce catecholamine
activity (Caldwell, 1970). The concurrent employment of animal models has provided
valuable models for examining the more detailed biochemistry and pharmacology of RAGE.
For instance, the possibility of a catecholamine role in RAGE-like behavior has been tested
using inhibitors of catecholamine biosynthesis such as alpha-methyltyrosine to block the
!16
Daniel J. Guerra, Valentina Colonnello and Jaak Panksepp
synthetic enzyme tyrosine hydroxylase, which rather consistently reduces aggressive behavior
of male mice made aggressive by prolonged social isolation procedures (Matte and Tornow,
1979). Partly this is surely due to the sedation promoted by this manipulation. Further
evidence suggested adrenergic-catecholamine regulation of aggression versus general stress
in both animal and human studies. In a standard resident-intruder test, wild-type rats exposed
to social stress by a defeat experience generally showed higher plasma norepinephrine and
epinephrine concentrations than control rats exposed to shock, i.e. a nonsocial stress
experience. A positive association between aggressive behavior level and catecholaminergic
reactivity to the stressors was also found (Sgoifo et al., 1996). In humans, a study of
preschool children confirmed this correlation between aggressive behavioral profile and
circulating catecholamine levels. This study showed also sex-related differences in
catecholamine metabolism and aggression, with the aggressive behavior pattern and levels of
epinephrine and norepinephrine excretion higher in boys than girls (Lundberg, 1983).
In both animals and humans the modulation of aggressive behavior has been further
investigated via administration of related pharmacological agents. In particular, a reduction of
norepinephrine levels via beta-adrenergic antagonists has consistently led to diminished
aggressive behaviors (Eichelman, 1981; O'Neil et al., 1986). In contrast, the block of
synaptic amine reuptake, as well as the inhibition of the enzyme that breaks down
norepinephrine, generally intensify anger outbursts, as demonstrated in studies employing the
administration of tricyclic antidepressants and monoamine oxidase inhibitor drugs,
respectively (Rampling, 1978).
Since norepinephrine is synthesized from dopamine, a direct association between
dopamine and aggression has been also investigated. To this end, several studies exploited the
potentiating effects of amphetamines which release both catecholamines from the nerve
terminalis. The amphetamines were found to act as either agonists or antagonists of mouse
aggressive behavior (Hodge & Butcher, 1975; Miczek & Haney, 1994) in a dose-dependent
way, with low doses increasing the aggression and high doses inducing an opposite effect
(Kramarcy et al., 1984), perhaps because of the induction of disruptive stereotypes. However,
because of the generic catecholamine release effects of amphetamines, these studies were not
conclusive in elucidating whether the increased aggression was related to norepinephrine or
dopamine. Therefore, clearer findings on the role of dopamine on aggression will be derived
from direct studies on dopamine receptors. Indeed, the administration of both direct dopamine
and dopamine agonists, such as the apomorphine and quinpirole, enhanced aggressive
behavior (Ossowska et al, 1996). Conversely, antagonists of dopamime D2 receptors produce
an opposite effect, with a reduction of aggressive behaviors. It is the case of the antagonist
sulpiride (Redolat et al., 1991), which diminishes feelings of anger in conjunction with
impairment in the recognition of angry facial expressions (Lawrence et al., 2002). Indeed,
most of the common dopamine blocking antipsychotic drugs that ameliorate aggression work
via D2 receptor antagonism, for example, as with risperidone (Rocca et al., 2002) and
clozapine (Lieberman et al., 2008).
Thus, a solid understanding of the role of catecholamines in RAGE in both animal
models, as confirmed in human studies, has emerged. There is little doubt that
catecholaminergic systems promote RAGE, with both norepinephrine and dopamine
decreasing behavioral thresholds for aggression, but neither promotes RAGE-anger in any
obligatory way. These neurochemistries have similar effects on many emotional behaviors.
This catcholamine connection has also been demonstrated indirectly by examining the
degradation patterns of the bioactive catecholamines. For instance, in both rodents and
humans inhibition of both catechol-O-methyltransferase (COMT) and monoamine oxidase A
(MAOA), enzymes that break down catecholamine, promote heightened aggression, a finding
confirmed by elevated levels of aggression in mice whose COMT or MAOA genes have been
!17
Neurobiology of RAGE and Anger
knocked out (Gogos et al., 1998, Cases et al., 1995). Thus, it is not too surprising that the
alleles that code for the low MAOA activity are positively related to aggressive behavior in
maltreated male children as well as in several psychiatric conditions (Caspi et al., 2002; Kim-
Cohen et al., 2006). To what extent this is induced via mutation or epigenetic phenomenon
(i.e. suppression of non-mutant alleles via promoter methylation) needs to be investigated. At
this point, it is clear that certain COMT and MAOA polymorphisms represent a basic
neurochemical phenomenon regulating the potential for RAGE (Volavka et al., 2004).
This also suggests how environmental factors can play a decisive role in psychiatric
aggressive disorders and their severity. The question remains to what extent aggressive
behaviors can potentiate pre-existing disorders and whether predisposition to hyperexcitable
RAGE circuitries provide fertile ground for emergence of psychiatric diseases. Linkage and
association studies suggest that a genetic vulnerability may play a role, but this predisposition
is not yet known to be the catalyst for the onset of disorders. Thus, even though such systems
are permissive for the expression of certain aggressive traits, they do not operate in obligatory
ways but always with reference to other contextual variables.
While the catecholamines generally facilitate aggressive behavior, the serotonergic
system generally inhibit RAGE expressions (Popova, 2008; Seo et al., 2008). As mentioned
above, there is an association between the reduced glucose uptake in the orbital prefrontal
cortex, an area implicated in inhibition of impulses and characterized by abundant
serotonergic innervations, and RAGE-related behaviors (Parsey et al., 2002). Moreover, low
brain serotonin activity is associated with high scores of aggressive behavior across the life
span (Kruesi et al., 1990).
Aggression inhibitory properties of serotonergic activity has been largely highlighted
with pharmacological approaches. Reduced aggressiveness has been observed using selective
serotonin re-uptake inhibitors that increase synaptic serotonin availability. In contrast,
reduced brain serotonin, whether through reduced availability of the serotonin precursor
tryptophan (Bell et al., 2001; Seo et al., 2008), as well or synthesis inhibition through
blockade of tryptophan hydroxylase, the first enzymatic step in serotonin synthesis, promotes
aggressiveness in both humans and other animals (Popova, 2008). Interestingly, a
serotonergic dysfunction has been associated with subtypes of depression characterized by
presence of anger attacks, and the treatment with antidepressants is effective in decreasing
anger levels in depressed patients (Nemeroff, 2002; Seo et al., 2008).
Thus, the overall expression of RAGE behavior, as many other primary emotions, is the
result of the interplay between serotonergic and catecholamine systems. This association is
also evident at connectivity levels, with the dopamine neurons receiving abundant
serotonergic projections. The serotonin 5-HT1A receptor is generally regarded as crucial in
the suppression of aggression and, more generally, of impulsive behaviors (Davridge et al.,
2004; Seo et al., 2008). Therefore, a dysfunction of the serotonergic neurotransmission,
especially at 5-HT1A receptors, may be associated to RAGE-related phenotypes (Chiavegatto
et al., 2001) at various levels of control within the hierarchical regulation of aggressive
irritability. For instance, compounds (sometimes called serenics) with a high affinity for the
5-HT1A receptors may reduce aggressive tendencies not only by toning down RAGE
circuitry, but also elevating thresholds for incoming anger provoking stimuli (for discussion,
see Panksepp, 1998, p. 202-203). Concurring with this finding, Positron Emission
Tomography (PET) imaging studies using a selective 5-HT receptor type 1A (5-HT1A)
antagonist showed a negative correlation between 5-HT1A binding in the amygdala and
prefrontal cortex and the scores in the Lifetime History of Aggression scale (Parsey et al.,
2002), suggesting decreases serotonergic inhibition of impulsivity/irritability in those
individuals.
!18
Daniel J. Guerra, Valentina Colonnello and Jaak Panksepp
However, it must again be emphasized that biogenic amines are widely represented in
the brain, controlling all emotional functions, so they by no means specifically regulate
aggressive urges. In sum, the catecholamines participate in global arousal, which include
elevated induction of defensive RAGE networks, while serotonin generally reduces such
urges. This knowledge provides some useful clinical tools for the regulation of anger type
irritability. However, so far no highly selective neurochemical pathway has been definitively
identified for persistent anger, but there are promising candidates among neuropeptides,
which may provide more specific pharmacological regulation of persistent anger-type
irritability.

NEURONAL PEPTIDES AS POTENTIAL SPECIFIC


REGULATORS OF AGGRESSION
Among the neuropeptides involved in defensive RAGE, the opioid peptides have
attracted great attention. The fascinating power of opioid activity in facilitating pro-sociality
(Panksepp, 1981, Panksepp, et al., 1984) and reducing defensive RAGE behavior has been
evaluated mainly by a pharmacological approach using agonists and antagonists of opioid
receptors. In this instance, in cat, the administration of Met5-enkephalin is able to suppress
defensive behavior through its action at PAG level (Shaikh et al. 1991; Weiner et al.,1991). In
the same direction, the administration of morphine, and other mu opioid agonist receptors,
generally produce robust anti-aggressive effects (Dyakonova et al., 2002; Puglisi-Allegra et
al., 1984). On the other hand, administration of opioid receptor antagonists, such as the
naloxone, can increase aggression behavior (Stolerman et al., 1975; Tidey and Miczek,
1992a,b; Dyakonova et al., 2000, 2002). Although certain forms of aggressions, such as inter-
male fighting, can be reduced with high doses of the opioid antagonists naltrexone (Winslow
and Miczek, 1988), this may simply reflect the fact that opioid antagonist reduce social
confidence in such encounters (Panksepp, et al., 1990).
Various other neuropeptides have interesting aggression modulating effects. Altered
aggression is routinely observed with other prosocial peptides such as oxyotcin and
vasopressin. These neuropeptides are involved in an ample spectrum of social contexts, and
hence it is reasonable that they would modify social aggression (Bales and Carter, 2003;
Heinrichs and Domes, 2008; Veenema and Neumann, 2008).
Animal and human data converge in indicating that female-prevalent oxytocin, with its
receptors generously present in the frontal and limbic areas, has a powerful inhibitory effect
on aggressive behavior in conjunction with a reduced general activation and anxiety
(Landgraf and Neumann, 2004; Huber et al., 2005), especially separation distress (Panksepp,
1992). Conversely, as discussed next, male-prevalent vasopressin exerts an opposite effect.
Human studies have revealed an inverse correlation between cerebrospinal fluid levels of
oxytocin and scores in Life History of Aggression scale (Lee et al., 2009a). Further, the
administration of oxytocin facilitates social trust (Kosfeld et al., 2005; Ditzen et al., 2008),
increases the threshold for reactivity to stress (Carter, 2003; Heinrichs et al., 2003), and, as
shown in fMRI studies, decreases neural limbic activation in response to presentation of
angry faces (Kirsch et al., 2005). Moreover, in animals, oxytocin lessens aggressive behavior,
such as infanticidal tendency in mice (McCarthy, 1990). More recently, thanks to genetic
manipulations, a more direct association between oxytocin and aggression has been found.
Knockout mice for oxytocin, in addition to the expected altered social motivation in infancy,
showed more aggressive behavior in adulthood (Winslow et al., 2000; Ragnauth et al., 2005).
Also the mammalian peptide hormone, Arginine Vasopressin (AVP) and its analogue in
other vertabrates, Arginine Vasotocin (AVT) appear to mediate several social behaviors
!19
Neurobiology of RAGE and Anger
(Goodson and Bass, 2001; Stribley and Carter, 1999), although its physiological role was first
described as a peptide hormone that regulates water homeostasis and blood pressure, as well
as the physiology of aggression (Caldwell et al., 2008). Central administration of AVP
facilitates aggression (Ferris et al., 1997; Caldwell and Albers, 2004), while AVP antagonists
inhibit rat aggressive behavior in classical resident-intruder tests (Ferris and Potegal, 1988;
Blanchard et al., 2005). With regard to human facial cues of aggression, electromyographic
(EMG) responses of the corrugator supercilii, (typically associated with inter-male
aggression) are increased in men given intranasal AVP (Thompson et al. 2004). Moreover, in
humans with an established history of aggression, cerebrospinal fluid (CSF) levels of
vasopressin are positively correlated with life history of aggression (Coccaro et al., 1998).
Thus, it would be interesting to observe the gene expression in relation to previous experience
of aggression. Indeed, in animals, the facilitating role of AVP in aggression is found
dependent on prior experience, indicating the involvement of a possible synaptic learning and
changing gene expression (epigenetic) regulations of aggressive tendencies. Moreover, as
evidenced in genetic studies, mice knockout for the AVP receptor displayed reduced
aggressive behavior in absence of any observed sensorimotor deficits. However, in these mice
the levels of aggressive behavior can be enhanced with experience (Wersinger et al., 2002;
Wersinger et al., 2007). It is especially noteworthy that there are sexual dimorphisms in AVP/
AVT systems in non-humans where more is produced in male vs. female subjects. It should be
noted that AVP association with aggression is only evident in males. Because of the sexual
dimorphism, it might suggest that the AVP receptor system or something downstream from it,
is different between males and females.
There are many neuropeptides that have been associated with negative sensations usually
because they either mediate a pain response (via vasoconstriction) or because they block the
nociceptive recovery system (e.g. delta and mu opiod receptors).Substance P (SP) is a
neuropeptide that appears to fulfill both roles (Shaikh et al.,1993). Substance P works on pain
associated neurons found on the dorsal ganglia and it belongs to the tachykinin neuropeptide
family, including a close relative, neurokinin A. While SP does not mediate the signaling of
acute pain, it seems essential for the full development of stress-induced analgesia and for an
apparent aggressive response to territorial challenge that could not be mimicked by other
agents, as shown in studies on SP knockout mice (De Felipe, 1998). SP appears to play a
critical role via signaling through the neurokinin-1 receptor that is abundant in the medial
hypothalamus where the downstream defensive-RAGE circuit from the medial amygdala
projects. Indeed, feline RAGE evoked by electrical stimulation of the medial amygdala is
attenuated by placement of the NK1 antagonist, CP-96,345 into the medial hypothalamus.
Thus, it is likely that the medial amygdala triggers defensive rage partly by SP synapses in the
medial hypothalamus (Shaikh et al.,1993). Likewise, central neurokinin antagonism studied in
rats showed reduced aggressive behaviors (Halasz et al., 2009).
Several other aggression-anger modulating neuropepties are on the horizon. For instance,
Neuropeptide Y, appears to have an effect on aggression in rats that is counterbalanced by
serotonin (Dierick and Greenspan, 2007). A knockout of the Y1 subtype of NPY receptor has
promoted aggressive behavior in mice (Emeson and Morabito, 2005). Another neuropeptide
system with a potential role in RAGE and aggression is the pituitary adenylate cyclase-
activating polypeptide (PACAP) which belongs to large family of processed and secreted
peptides including glucagon, and growth hormone-releasing factor (Arimura, 1998), operating
through G-protein-coupled receptors (Harmar et al., 1998), with emerging implications for
regulation of aggression and anger (Nicot et al., 2004).
Overall, many of the neuropeptides may exert their effect on RAGE via the
GABAenergic response generated in the hypothalamus. Both defensive rage and predatory
aggression depend on inhibitory GABAergic systems within the hypothalamus and excitatory
!20
Daniel J. Guerra, Valentina Colonnello and Jaak Panksepp
gluatmatergic pathways in the PAG. In the midst of all this complexity, we find steroidal
controls that modulate many of these systems in gender specific ways, as already seen with
the capacity of oxytocin and vasopressin, whose gender-differentiates expressions in the brain
are steroid regulated, to reduce or facilitate aggression respective. Also, considering the well-
replicated fact that males are more aggressive than females, is noteworthy that the
testosterone analogue nandrolone decanoate was injected into male rat brain can increase
RAGE promoting SP levels in the amygdala, hypothalamus, striatum, and periaqueductal gray
(Hallberg et al., 2000). The steroid link to aggression has been widely studied, albeit still
poorly understood, especially in terms of the underlying psychological processes that are
promoted or inhibited.

THE STEROIDS CONNECTION TO AGGRESSIVE IRRITABILITY

The fact that the vast majority of reported acts of aggressive acts in humans and many
other mammals involve males has often been seen as support for a linkage between
circulating testosterone and sensitivity to anger. Indeed, abundant research suggests a degree
of correlation between serum testosterone and human aggression (see Archer, 1991 for
review). Much of this association has been derived from contrasting aggressive vs. non-
aggressive control groups of young men. Even among women there seems to be some
correlation between testosterone and violent behaviors (Dabbs et al., 1987; Dabbs and
Hargrove, 1997). However, the effects of exogenous testosterone on human aggression are
inconclusive. Both increased aggression (Kouri et al., 1998) and no such effect have been
reported (Anderson et al., 1992; Tricker et al., 1996). No doubt, the effects of testosterone
interact strongly with background personality characteristics, perhaps elevating aggression
only in frustrated males who are already chronically irritable.
Several lines of evidence suggest that testosterone is not primarily associated with
feelings of anger but rather other forms of aggression such as high mental energy levels,
dominance, and hence, under the right environmental circumstances, inter-male aggression.
As mentioned, RAGE is accompanied by strong negative affect, while testosterone appears to
generally promote positive feelings in hypogonadal men. In fact, elevated self-esteem with a
positive outlook are commonly promoted by pharmacological doses of testosterone
(Zitzmann, 2006). At times, the administration of testosterone actually improves male
emotional state toward compassion and consideration of others depending on ones intrinsic
temperament and permissive situational factors. In fact, at times testosterone can diminish
aggression and other “negative’ emotions while relieving aspects of general depression and
fatigue (Kanayama and Seidman, 2007). An intriguing paper published some years ago
focused on examination of two personality characteristics (dominance and anger) and their
relationship to hormone level in over 1700 naturally aging males. Scores on the Jackson
Personality Research Form (Dominance subscale) and the Spielberger Anger Expression scale
were regressed against the serum concentration of several steroid hormones including
testosterone, dihydrotestosterone, and cortisol. The “dominant” male personality, in
association with strong assertive behavior correlated with serum androgen concentration
(Gray et al., 1991).
Many studies have also pointed to the role of ethanol in potentiating the effects of
testosterone on anger in humans (Chermack and Giancola, 1997; Brismar and Bergman,
1998). Indeed, higher testosterone levels have at times been observed in alcoholics exhibiting
violent anti-social behavior, but neither the correlation between alcohol consumption and
testosterone nor their link to anger and violence has been straightforward (Bergman and
Brismar, 1994; Virkkunen et al., 1994).
!21
Neurobiology of RAGE and Anger
Many others studies have found inconclusive relationships between alcohol and
testosterone levels suggesting that aggressive behaviour is not consistently linked to high
circulating testosterone and/or alcohol consumption in humans (Walter et al., 2007).
On the other hand, there are also quite a few reports that androgenic anabolic steroids
(AAS) may promote an aggressive behavior that has been characterized as steroid or "roid
rage” (Galligani et al., 1996). In these cases, testosterone has typically been elevated by
several orders of magnitude beyond normal physiological levels. Likewise, in animal studies,
with administration of steroids at very high, non-physiological dosages, enhanced aggression
has been evident under certain testing conditions. For example, pubertal rats receiving AASs
respond more aggressive in social contexts toward other intact males (Farrell and McGinnis,
2003). In a similar study, male rats treated with pharmacological doses of testosterone
respond by behaving more aggressively to a host of environmental cues as compared to non-
treated controls, suggesting that in the presence of certain environmental challenges steroid
treated rats can become chronically aggressive (McGinnis, 2004 and references therein).
There are indications that rodents administered testosterone and nandrolone, but not
stanozolol exhibit higher levels of aggressive behavior than their placebo counterparts
(Schlussman et al., 2000). This result is interesting given the excessive use of stanozolol (aka
Winstrol) in body builders and athletes. Stanozolol has a very similar structure to testosterone
differing only in the 17 alpha carbon alkylation rendering it more water soluble and therefore
available and perhaps less resistant to metabolic breakdown. This points to an important
caveat in pharmacological research especially in neuroscience. Compounds of identical or
closely related structure to naturally occuring neuro-active substances in the brain, when
administered at non physiological doses can have profoundly different effects than natural
levels of endogenously produced substances. Thus, the actual cause and level of occurrence
of ste-“roid” rage in humans may or may not be directly related to the steroid structure but
more so to the ectopic (i.e., non-physiological) administration of the foreign substance
(Kindlundh et al., 2003). There is also usually rather little information provided regarding the
psychological profiles of anabolic steroid users, with many perhaps already predisposed to
aggression. Because of such undefined parameters, the effects of exogenous steroids on
human aggressiveness remain ambiguous. Generally, subjects receiving exogenous
testosterone at physiological doses rarely exhibit elevated aggression (Trenton and Currier,
2005), but it is equally clear that there is something about the normative male temperament
that predisposes both humans and animals toward elevated aggressive activities. Certainly,
testosterone can sensitize the RAGE circuitry of the brain (Kruk, et al. 19xx)
In comparison to proto-typical male steroids (i.e. androgens), relatively little work exists
on the endogenous or exogenous effects of female steroids on aggressive behavior. Although
there are a few studies in which estrogens have been positively linked to aggression in animal
models (Simon and Whalen, 1986; Hilakivi-Clarke et al., 1997), human studies generally find
reduced sexual aggressiveness (Bradford, 1983) and dementia-related aggression but not
verbal abuse, in elderly men ( Kay et al., 1995; Shelton and Brooks, 1999). Overall, if
anything, the prototypical female hormones, i.e. estrogen, progesterone and oxytocin, tend to
inhibit aggressive behaviors (e.g, Eriksson et al., 2003; Tordjman et al., 2003; Lee et al.,
2009a).
In summary, the role of physiological levels of testosterone or other male steroids in
anger feelings and behaviors remain to be well established, even though the fact that
aggressive behaviors are elevated in males is not in dispute. Clearly, psychological studies in
humans have been well supported by animal studies linking the male sex to higher potentials
for aggression. Thus, there is enough "smoke" in this area of research, that further
investigations are warranted not only for the physiological end products of steroid metabolism
but also associated neural mechanisms. For instance, since gender differentiation occurs in
!22
Daniel J. Guerra, Valentina Colonnello and Jaak Panksepp
utero in mammalian development it is important to consider the ontogenic factors involved in
the dimorphism of aggressive behavior between males and females even during gestation. In
rodents, sexual differentiation of the brain appears to be regulated by the conversion of
testosterone to estrogen during the perinatal time period. Recently neuropeptides, such as
those produced by the progranulin (PGRN) gene, have been identified which are selectively
expressed during rat brain masuclinization that may be linked to male aggression in the rat.
Male mice with targeted disruption of the PGRN gene display less aggression and more
anxiety than their normal counterparts. Significantly, transcription of the serotonin receptor 5-
HT1A, often associated with the inhibition of aggression and anxiety, was reduced in the
hippocampus of PGRN-deficient mice, with no accompanying changes in testosterone levels
(Kayasuga et al., 2007).

RAGE AND IMMUNE-SYSTEM

Neuropeptide expression as well as the interacting components of the dopaminergic,
steroid, glutaminergic and GABAergic pathways all intersect biochemically along several
important neural networks found in the hypothalamus, amygdala, and periaqueductal gray and
other brain regions including the cortex. These brain regions also involve the immune system,
both innate and acquired. The brain as the seat for affective neurochemical and
neurophysiological phenomenon is a system in constant activity requiring memory and
programming. Since the immune system is in place to carry out these processes and since
immune cytokines play a major role in tissue regeneration, protection and removal, it is
possible that innate and to a larger extent, acquired immune responses, help shape the
affective neurological network including that of aggression and RAGE. Considering the
possible link between RAGE circuits and depression, it is also worth noting that the
relationship between cytokines and depression is well developed (Anisman, et al., 2008;
Miller, et al., 2009).
Besides classical neuropeptides acting upon RAGE circuitry, other reports have
demonstrated an involvement of certain peptide-cytokines. These include a class of immune
system peptides called interleukins, which play a role in inflammation. An Interleukin-1beta
(IL-1β) causes the release of hypothalamic serotonin. It was demonstrated that IL-1Beta could
potentiate feline defensive RAGE via a serotonin receptor mediated mechanism that included
the interplay between the hypothalamus and the PAG (Hassanain et al., 2003). This was later
confirmed to be specific to defensive RAGE after injecting IL-1 beta directly into the PAG
(Bhatt and Siegel, 2006). Other reports are making it clear that brain-derived cytokines are
involved in RAGE circuitry (Bhatt et al., 2005) and most recently in humans (Moons et al.,
2009). That this immune responsive system may have more interesting roles in RAGE
circuitry awaits further inquiry.
All this suggests many new avenues for the control of significant anger and aggression is
psychiatric disorders. Perhaps the most immediate possibility is the reduction of anger in
human and other animals using the medically approved SP antagonist, aprepitant (Panksepp
& Harro, 2004). There are an increasing number of studies suggesting that this kind of
manipulation may be highly effective in managing undesired levels of anger. A recent review
has emphasized the neuroanatomical and behavioral association of the SP/NK-1 ligand/
receptor complex in aggression (Katsouni et al., 2009). Studies looking at the interaction of
this molecular system and stressful environmental cues may inspire animal research studies
and perhaps clinical and pharmacological discoveries.
!23
Neurobiology of RAGE and Anger
FUTURE PROSPECTS: SUMMARY OF SOME GENETIC COMPONENTS
OF THE RAGE PHENOTYPE

In the previous sections, we mentioned several studies showing the genetic component of
elevated RAGE-related phenotypes. Here, we will summarize and contextualize the studies
reported above and will present some of the more recent findings.
Studies on genetic basis of psychiatric conditions showed the involvement of multiple
genetic loci is irregularly expressed in a phenotypically and developmentally progressive
manner. These studies adopted a genetic-association approach, which is aimed at identifying
the specific genes and the candidate variants within each gene, implicated in the vulnerability
and aetiology of psychiatric phenotypes and personality traits (Reichborn-Kjennerud, 2008).
Yet, despite these studies that have identified a variety of targeted genes involved in
psychiatric disorders, a precise isolation of specific genes for distinct syndromal categories
seems far from being achieved. Nonetheless, a promising contribution from molecular genetic
studies may be generated by investigating genetic make-up of distinct basic emotional
phenotypes, such as those related to RAGE system. Indeed, these systems have clear linkage
to specific neural circuits more than the general syndromal categories. Also, anger is present
transversally across syndromes, so an acquisition of knowledge of specific emotional
phenotypes may lead to a better understanding of human psychopathology.
To date, the genetic component of RAGE-related phenotype has been demonstrated both
in human and animal studies. In particular, from a historical perspective, the earliest research
focused on the heritability of aggression and aggressiveness predisposition. In humans it has
been studied in adult populations of twins exposed to different environments (Coccaro et al
1993; Rushton et al 1986; Tellegen et al 1988), while in animals, the anger-related heritable
factors have been highlighted by manipulating genetic background through selective breeding
procedures. These studies confirmed the findings based on the pharmacological approach: an
increase of levels of aggression has been documented in animals selectively bred for higher
brain dopamine levels, sensitivity to cholinergic agonists, and selective loss of 5-HT axons
(Lee, 1991; Pucilowski et al., 1991; Lyons et al., 1999). The genetic association between
endogenous opioid concentrations and aggression also has been detected studying inbred
mouse strains previously selected for different levels of aggressive behavior. In particular, a
negative correlation has been evident between brain enkephalin and endorphin levels and
aggression scores in the sixth generation of eleven inbred mouse strains, supporting the
antiaggressive effects of opioids (Tordjman et al., 2003). Lines of mice selected for high
aggressive behaviour were also more susceptible to early immune challenges and showed a
stronger immune sensitivity compared to lines selected for low aggressiveness, suggesting a
linkage between immune responsiveness and aggression (Petitto et al., 1994; Granger et al.,
2001).
More recent studies based on specific genetic manipulation approach have further
elucidated the genetic basis of anger. These studies, exploiting the recent techniques, adopted
chromosomal alteration and mutation procedures involving alterations of selective
neurotransmitters involved in the RAGE system. In this instance, we already mentioned the
anger-related responses of PGRN and NPY knock-out mice. As highlighted, the serotonergic
system plays a key role in modulation of aggression (indeed, as noted earlier, all emotional
behaviors); thus, mutant mice lacking of 5-HT receptor showed enhanced aggressive behavior
(Saudou et al., 1994). Elevated aggression has been demonstrated also in male mice that have
either the COMT or the MAOA gene knock-out. Since aggressive behavior is exacerbated by
catecholaminergic activity, it is not surprising that a decrease in COMT and MAOA activity
would indirectly enhance aggression, as well as that mice selected for high aggressive
behavior had also higher levels of dopamine (Lee, 1991). Increased aggressiveness and
!24
Daniel J. Guerra, Valentina Colonnello and Jaak Panksepp
altered social motivation has been reported also for oxytocin (Ragnauth et al., 2005; Winslow
et al., 2000) and enkephalin-deficient knockout mice (König et al., 1996), supporting the
hypothesis of a genetic association between aggressive behaviour and brain oxytocin and
endogenous opioids, such as the enkephalins.
Such evidence has been mainly based on single-gene mutation approaches. However,
interest in “natural” variation at the phenotype level encouraged further studies to look for the
natural allele genetic variations involved in the expression of individual differences in
aggressive behavior. For instance, Brodkin and colleagues (Brodkin et al., 2002), interested in
investigating individual and strain differences in mice, used a two-generation outcross–
backcross breeding procedure followed by a quantitative trait loci analysis. The authors
identified quantitative trait for inter-male aggression on distal chromosome 10 and proximal
chromosome X. The possible genes have been identified in a specific subunit gene (the
diacylglycerol kinase alfa), highly expressed in several areas, among them in the
hippocampus and cerebellum, and the glutamate receptor subunit AMPA3 gene. The findings
of natural genetic individual differences in predisposition to anger-related responses seem
supportive of the hypothesis of natural genetic basis for specific emotional phenotypes.
Research aimed at identifying the potential linkage between RAGE-like phenotype to
specific genotype have been extended to humans. Concurring with the findings from animal
studies, COMT and 5-HTTPR genotype were found associated to enhanced aggressive
behavior in humans (Strous et al., 1997; Han et al., 2004). The RAGE phenotype resulted
linked also to an upergulation of DARP-32 (dopamine and cAMP regulated phosphoprotein
of 32 kDa, DARPP-32) T allele (TT) in a study on non psychiatric population. The protein
phosphatase 1 DARP-32, which with its inhibitory function, is involved in maintaining the
dopaminergic neurotransmission (Reuter et al., 2009; Torres et al., 2009).
Along similar lines, the linkage between anger/hostility personality trait and genetic
variation has been confirmed in recent studies on variation of T-box 19 locus, showing that
this gene is implicated in the predisposition for the anger trait and depressive symptoms. It is
worthwhile to consider that the T-box 19 is expressed in some pituitary cells and is involved
in the hypothalamic-pituitary-adrenocortical axis, and so is associated with vulnerability to
stress (Wasserman et al., 2007). Other studies, including natural variations of RAGE-like
phenotypes, demonstrated that homozygosity for the U allele in the TPH gene was associated
with higher anger-related responses, compared to homozygosis for the more common L allele.
On the other hand, the TPH heterozygotes showed intermediate level of anger (Manuck et al.,
1999; Rujescu et al., 2002). What is interesting to note is that the TPH is among the genes
implicated in the serotonin system, which, as mentioned, has dense innervations in the
RAGE-regulating orbital prefrontal cortex.
Besides these genetic associations, male knock-out mice deficient in neuronal nitric oxide
synthetase show aggressive behavior not observed in female counterparts (Kriegsfeld, et al.
1997). This effect seemed to require the presence of testosterone. Nitric oxide is a powerful
signaling molecule in animals and plants that functions via control over haeme containing
polypeptides including G-proteins which act as transcription factors (Kitamura, et al. 1996).
Even though culture and the social environment plays a relevant role in expression and
regulation of anger, these findings from human genotyping are consistent with the animal
studies that highlighted the linkage between the predisposition for RAGE related phenotypes
and specific genotypes. The studies described here elucidated the role of specific genes in
expression of aggressive phenotype. Further understanding and identification of a more
exhaustive and integrated genetic profile of RAGE phenotype would be achieved by studies
on multi-gene approach.
!25
Neurobiology of RAGE and Anger
THE EPIGENETICS OF AGGRESSIVE PHENOTYPES
One more layer of this hierarchical machinery of regulation needs too be addressed and it
involves the process of epigenetics. Genetic and “epigenetic” phenomenon shape brain
neuronal activity and the behavioral and mental phenomena that ensue. While the mammalian
genome establishes the template for empirically discernable developmental and behavioural
patterns, a more complex and variable sequence helps to produce the final phenotype. This
latter “epigenetic” phenomenon has increasingly become the subject of mammalian
developmental biology and gene expression. This is nowhere more apparent when analyzing
parental imprinting. The biochemistry of epigenetics involves several covalent modifications
of nuclear chromatin as well as post-transcriptional gene silencing.
Among these modifications are methylation of the C5 atom on cytosine residues found in
CpG islands associated with promoter elements, methylation, acetylation, ubiquination and
phosphorylation of cohering histones and the processing of double-stranded RNA in the
generation of siRNA involved in gene silencing (Caifa et al., 2009). The mechanisms of these
epigenetic phenomena have been described and they include the activities of
methyltransferases, acetyl transferases, kinases, phosphatases, demethylases, deacetylases, E3
ubiquitin ligases and certain discrete double-stranded RNase enzymes. The substrates for
these reactions are either chromatin or in the case of the RNase activities, double-stranded
mRNA. S-adenosyl methionine (SAM or AdoMET) is the recognized nuclear methylation
agent, deriving the methyl group from folic acid derivatives. Acetyl CoA is used in
acetylation of chromatin associated histones in the process of chromatin remodeling which
generally enhances gene expression downstream from ligand/receptor mediated activation of
the complex which may be in association with the nuclear ubiquitin/proteasomal pathways.
Nuclear-associated posttranslational modifications of histone carboxy termini clearly alter
chromatin structure and function. The major effect is a pronounced change in the physical-
chemical accessibility of DNA binding proteins to unwind the double helix and transcribe
RNA. These covalent modifications are reversible but sometimes leads to a temporary but
complete removal of histones from the chromatin complex thus inducing for a time in the cell
cycle constitutive gene expression. Indeed, while methylation tends to dissociate histones
from the chromatin complex, demethylation tends to favor non-transcribable chromatin
rearrangement. Besides the specificity of the methyltransferases and acetyl transferases on
certain histone polypeptides, there is also a specificity at the amino acid sequence level. To
generate changes in reactivity of chromatin to remodeling, only certain covalently modified
histone amino acid residues play a role. The discrete biochemistry of these epigenetic
modifications are lysine methylation, acetylation and ubiquination, serine phosphorylation
and arginine methylation (Strahl and Allis, 2000). These covalent modifications effect DNA
accessibility to various proteins and they alter protein: protein interactions among chromatin-
bound histones and other polypeptides.
The “Histone Code Hypothesis” asserts that covalent modification of chromatin-bound
histones is communicated to a host of nuclear proteins to provide a directive for discrete
chromatin molecular dynamics and gene expression control. The theory suggests that other
proteins and protein complexes can distinguish and indeed interpret histone modifications.
Communication of the “Histone Code” to the nuclear machinery of transcription ultimately
controls gene expression or silencing, heterochromatin formation, DNA replication and even
chromosome segregation (Jenuwein and Allis, 2001).
Most if not all of these epigenetic modifications are heritable changes in gene expression.
Even though DNA sequence modification does not generally occur there are reports where
amplification of nucleotide repeats can be proximal to DNA methylation (Jenuwein and Allis,
2001). Whether or not this is a common phenomenon in acquired epigenesis may be
!26
Daniel J. Guerra, Valentina Colonnello and Jaak Panksepp
significant in human disease. What is clear is that many developmental disorders as well as
cancer, age-related illnesses and various brain disorders are linked to changes in DNA
methylation. Epigenetic modifications (especially DNA methylation) provide a fine-tuning on
gene expression. Induced hypermethylation by xenobiotics as well as hypomethylation are
linked to these diseases.
Besides various diseases, epigenetic phenomenon is developmentally programmed. As
such, epigenetic control over gene expression and cell differentiation as well as tissue
formation and neurogenesis have been extensively reported. Epigenetics also plays a major
role in the immune response. In fact mechanisms including CpG methylation and various
histone modifications are basic biochemical phenomena regulating the mammalian immune
response. Chromatin remodeling as well as the cohering epigenetic control over
transcriptional processes have been shown to help regulate cytokine expression and secretion
as well as antigen processing and T-cell differentiation (Sawalha, 2008). We have already
discussed the role of cytokines in inducing the RAGE circuitry. As it turns out, transcriptional
control over cytokine gene expression is a key element in the regulation of the immune
response. Epigenetic phenomena including stress play a large role in the immune associated
control over cellular differentiation including that occurring in the mammalian brain (Vanden
Berghe et al., 2006).

CONCLUSION
Although the brain clearly has primary-process genetically inherited mechanisms that can
promote RAGE and other kinds of aggression, it is especially important to focus on the fact
that secondary learning and tertiary cognitive-thought processes, even culture, can contribute
the final aggressive phenotype (Pahlavan, 2004). (Again, please note that here the primary-
process emotions are regarded as the expression of subcortical evolutionarily provided basic
systems, while the secondary-process emotions find their manifestation in the simplest forms
of emotional learning, and tertiary processes, emerging from higher neocortical areas, are
expressed in culturally constructed emotions). Obviously, many aspects of aggressive
tendencies are obviously learned or acquired through higher brain functions rather than
genetically predetermined, especially in humans who are evolutionarily designed to be
cultural creatures and have the higher mental capacities to regulate their instinctive-animalian
urges.
Indeed, there have long been working hypotheses or theories that suggest that aggression
is largely a learned behavior, which is certainly not true. There are inbuilt aggressive
mechanisms in the brain. This leads to the question of when in development will excessive
experiences with one's RAGE circuitry have life long influences. It has been suggested that
small children can learn aggressive behavior early while others develop this tendency later in
life on to early adulthood, but we currently do not know whether early-experiences with
excessive anger promotes an impulsive phenotype later in life. Indeed the World Health
Organization in a paper examining anger and aggression persuasively argued that the
overwhelming majority of young people learn aggressive behaviors as adolescents and that
there is no clear association with their early childhood development (Tremblay, 2008). This
does not mean that animal studies and the essential role of universal neurochemicals in
signaling and foundational brain circuitries for affective-emotional states do not play a role.
However, their influences may be most striking in psychiatric disorders.
!27
Neurobiology of RAGE and Anger
Also, different rules may apply to more instrumental forms of aggression. Practically all
forms of human predatory aggression, whether personal violations, arising from unmet
desires, such as rape, or pre-mediated aggressions in the economic marketplace, are always
colored by an enormous amount of past learning. The SEEKING system, from which
predatory-desires arise, is a premier general-purpose learning mechanism of the brain
(Panksepp & Moskal, 2009). On the other hand, more impulsive forms of aggression, as
emerge most commonly with the arousal of ancient mammalian RAGE systems, operate most
readily when higher cultural and cerebral influences are "out of mind" so to speak.
Just as in disease, a predisposition is necessary for the presentation of bodily disorders,
the same goes for neural conditions that promote excessive aggression in psychiatric
disorders. We would suggest that the most important predisposing conditions of the brain are
excessive activity of RAGE systems for all kinds of impulsive and emotionally reactive
aggression, and culturally inappropriate SEEKING urges in more predatory forms of
offense--ranging from stalking to psychopathic offensiveness. However, given that all mind
Brain functions are regulated via epigenetic phenomenon, including perhaps, as we have
speculated, both acquired and innate immunity control of brain tissue differentiation, we
would suggest that RAGE as well as all other innate, primary-process, emotional circuitry is
molded by epigenetic programs during early development, perhaps some of them immune-
based. The upshot of this would be that culture must be as attentive to the early affective
developmental landscapes in which children's emotional systems are expressed as in their
cognitive growth (Panksepp, 2001). Parental disapproval of aggression can clearly moderate
children's tendencies to be assaultive (Berkowitz, 2004).
Anger can be characterized as a long-term behavior with episodic presentation. This
requires programming, memory, and the continued reinforcement of specific neuronal
circuitry such as that observed in biogenic amine and neuropeptide pathways among others.
The concentration of neurochemically active substances changes diurnally with one's
circadian rhythm. There is also a natural fluctuation and gradient accumulation of
neurochemicals related to age, sex, experience, imprinting (as in epigenetic phenomenon),
stress level, as well as various drugs and life habits such as alcohol consumption. What is
emerging from this correlative conjunction is a new fusion of behavioral and biological
sciences that includes the recording of a biochemical interactome accomplished via pattern
recognition receptor systems.
To understand the biological psychology of RAGE and other emotions we may
eventually be able to implement dynamic systems approaches (Panksepp, 2000) which
incorporate an emerging theory that begins to combine neurogenesis, ontogeny of brain,
neurotransmitter and hormonal development as well as the environmental (re)-programming
of gene expression (epigenetics, chromatin remodeling). This in no way diminishes the
importance of early childhood rearing and personal emotion regulation and intelligence in
moderating the biological dispositions to behave in anti-social ways.

ACKNOWLEDGEMENT
The construction of this manuscript was done while the research of the authors was
supported by a Hope for Depression Research Grant.

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