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Prog. Neum-Psychaphan~ca1. &Bud. Psychiat. 2001, Vol. 25, pp. 91-140 Copyright 0 2001 Elsemer Science Inc.

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BRAIN STRUCTURES AND NEUROTRANSMITTERS REGULATING AGGRESSION IN CATS: IMPLICATIONS F’OR HUMAN AGGRESSION

THOMAS R. GREGG’ AND ALLAN SIEGELIs

‘Department of Neurosciences and * Department of Psychiatry, Medical Sciences Building, Room H-5 12 University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ, USA

(Final form, December 2000)

Contents

Abstract 1. Introduction 1.1. Relevance of Feline Aggression to Human Aggression 2. Research Methods 2.1. Two Forms of Aggressive Behavior 2.2. Advantages of the Cat as a Model 2.3. Stimulation Techniques 3. Neuroanatomical Substrates of Defensive Rage and Predatory Aggression 3.1. Defensive Rage 3.1.1. Hypothalamus 3.1.2. PAG 3.2. Predatory Behavior 3.3. Modulatory Pathways 3.3.1. The Amygdala 3.3.2. Other Regions of the Liibic System 4. Neurotransmitter Functions 4.1. Excitatory Neurotransmitters 4.1.1. Excitatory Amino Acids 4.1.2. Neurokinins 4.1.3. Cholecystokinin 4.1.4. Norepinephrine 4.1.5. Doparnine 4.2. Inhibitory Neurotransmitters 4.2.1. Opioid Peptides 4.2.2. The Role of GABAergic Neurons and Receptors in the Hypothalamus: Reciprocal Inhibition

Within the Hypothalamus. 4.2.3. Serotonin 5. Conclusions 91

92

Acknowledgements References

T.R. Gregg and A. Siegel

Gregg, Thomas R. and Allan Siegel: Brain structures and neurotransmitters regulating aggression in cats: Implications for human aggression. Prog. NeuroPsychopharmacol. & Biol. Psychiat. 2001,25, pp. 91-140. 82001 Elsevier Science Inc.

1. Violence and aggression are major public health problems. 2. The authors have used techniques of electrical brain stimulation, anatomical-immunohistochemical techniques, and behavioral pharmacology to investigate the neural systems and circuits underlying aggressive behavior in the cat. 3. The medial hypothalamus and midbrain periaqueductal gray are the most important structures mediating defensive rage behavior, and the perifomical lateral hypothalamus clearly mediates predatory attack behavior. The hippocampus, amygdala, bed nucleus of the stria term&@ septal area, cingulate gyrus, and prefrontal cortex project to these structures directly or indirectly and thus can modulate the intensity of attack and rage. 4. Evidence suggests that several neurotransmitters facilitate defensive rage within the PAG and medial hypothalamus, including glutamate, Substance P, and cholecystokinin, and that opioid peptides suppress it; these effects usually depend on the subtype of receptor that is activated. 5. A key recent discovery was a GABAergic projection that may underlie the often-observed reciprocally inhibitory relationship between these two forms of aggression. 6. Recently, Substance P has come under scrutiny as a possible key neurotransmitter involved in defensive rage, and the mechanism by which it plays a role in aggression and rage is under investigation. 7. It is hoped that this line of research will provide a better understanding of the neural mechanisms and substrates regulating aggression and rage and thus establish a rational basis for treatment of disorders associated with these forms of aggression.

Kevwordg aggression, cat, GABA, hypothalamus, neurotransmitters, neuropeptides, periaqueductal gray, substance P.

Abbreviations: -, inhibition; +, excitation; 2-DG* “C-2-deoxyglucose; WIT, 5-hydroxytryptamine (serotonin); AAA, anterior amygdaloid area; AB, basal nucleus of amygdala; AH, anterior hypothalamus; AL, lateral amygdsloid nucleus; AM, medial amygdala; M, anterior medial hypothalamus; AMPA, w- a-amino-3-hydroxy-5-methylisoxazole&proprionic acid; Amy, amygdala; AP-7, w-2-amino-7- phosphoheptanoic acid; BNST, bed nucleus of the stria terminalis; CCK, cholecystokinin; CE, central amygdala; Ch, optic chiasm; Cl, claustrum; CNQX, 6-cyano-7-nitroquinoxalin-2,3-dione; DA, dopamine; DAME, @XAla(2)]methionine enkephalinsmide; dBB, diagonal band of Broca; DOI, l-(2,5-diiethoxy-4- iodophenyl)-2-aminopropane hydrochloride; DR, defensive rage; EAA, excitatory amino acids; ENK, enkephalii; Fx, fornix; GABA, gamma-amino butyric acid; Gi, i subtype of G-protein; HL, lateral hypothalamus; HP, posterior hypothalamus; HVM, ventromedial hypothalamus; LH, lateral hypothalamus; M, medial amygdala; hlE, medial amygdala; ME& medial hypothalamus; n., nucleus; NE, norepinephrine; NK-1, NK-2, NK-3, neurokinin-1,2,3; NMDA, n-methyl-d-aspartate; OC, optic chiasm; OT, optic tract; PA, predatory attack; PAG, periaqueductal gray; pMPP1, 4-iodo-N-[2-[4- (methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl&enzamide hydrochloride; RE, nucleus reuniens; SP, substance P; subst. innom., substantia innominata; THC, A’-tctrahydrocannibinol; VMH, ventromedial hypothalamus; VTA, ventral tegmental area; S-HTIA, subtype IA of the serotonin receptor.

Neural substrates of aggression in cats

1. Introductiol!

Violence and rage have emerged as major social and public health problems, especially in recent years.

Recently, there have been more than 3,000,000 violent crimes committed in the U.S. annually (Reiss et

al., 1994) resulting in human suffering as well as costs of millions if not billions of dollars to society.

These problems may be ameliorated by understandiig the root causes of violence. One strategy that has

been adopted to identify such root causes is to develop an understandiig of the neurobiology of human

aggression. It is our position that this can best be achieved by identifying the underlying neural circuitry

and neurotransmitter receptors. We believe that such an understanding will provide the rational basis for

development of treatment of disorders associated with human aggression and violence. The purpose of

the present paper is to describe the research that has been conducted in our laboratory and elsewhere that

has addressed these issues.

1.1. Relevance of Feline Aneression to Human Aggression

Violence is ir&enced by cultural, environmental and social factors which shape the manner in which it

is expressed @on, 1987). Nevertheless, there is a common neural substrate underlying all forms of

violence. We hold the view that the neural basis of aggression in humans resembles that in animals such as

the cat and the forms of aggression seen in humans parallel those observed in animals. Evidence

supporting this view includes the results of recent studies conducted in a population of children (Vitiello

et al., 1990; Vitiello and Staff, 1997). These authors proposed a dichotomous classitication of violent

behavior derived from the classification scheme used in our cat models of hypothalamically-ehcited

aggression, which categorizes aggression as being either defensive rage or predatory attack behavior. In

particular, Vitiello et al. (1990) developed and validated an observational rating scale, which was applied

to children and which clearly dibrentiated affective aggmssion (i.e., impulsive, overt and unplanned in

nature; equivalent to defensive rage) from predatory aggression (i.e., planned, goal-directed, emotionless,

hidden and not preceded by autonomic arousal). These authors found a bimodal distribution of scores,

one reflecting individuals who displayed affective aggression, the other reflecting individuals who

displayed predatory or a mixture of predatory-affective aggression. Furthermore, several other authors

have provided evidence for similar dichotomous classification systems in children (Loeber and Schmaliig

1985, Dodge and Coie 1987), including a most recent study (Malone et al., 1998). Such evidence

supports the view that the behavioral expression of human aggression is similar to that in cats. We do not

assert that only two forms of aggression exist. Nevertheless, we do hold the view that the behavioral and

neural characteristics of predatory attack and defensive rage are analogous in humans and cats.

94 T.R. Gregg and A. Siegel

Studies in human adults support this view aa well. Much of the behavioral as well as clinical (see

paragraph below) research concerning the nosology of aggression in adults has focused upon defensive

rage (Buss and Perry, 1992). However, despite the problems of obtaining accurate self-reports, most

recently, two tindings have provided evidence for predatory-like behavior in adults (Meloy, 1997;

Jacobson and Gottman 1998). In one report, the case of a mass murder by a 35year-old male was shown

to be consistent with predatory aggression (Meloy, 1997). A second report focused upon the typology of

perpetrators of spousal abuse (Jacobson and Gottman 1998). The perpetrators were classified into one

of two categories: the first approximated defensive rage as these individuals displayed their emotions

impulsively with increased sympathetic arousal, while the second approximated predatory aggression as

these individuals displayed “calculated and cunning” behavior with decreased autonomic arousal.

An expanding body of data indicates that aggressive behavior appears as a component of numerous

clinical disorders associated with abnormal brain function, including Alzheimer’s disease, affective

disorders, schizophrenia, tertiary syphilis, brain tumors, temporal lobe epilepsy, encephalitis, and normal

pressure hydrocephalus (Bear, 1979; Falconer, 1973; Heimburger et al., 1978; Hood et al., 1983;

Monroe, 1985; Monroe, 1978; Gunsted, 1969; Piacente, 1986; Serafetinides, 1965; Sweet, et al.,1969;

Taylor, 1983; Aarsland et al., 1996). Such behavior usually falls into the category of defensive rage.

Most notable is the aggression referred to as “episodic dyscontrol,” which is seen in patients with

temporal lobe epilepsy or hypothalamic tumors. Typically, such patients display an explosive personality

and may be physically or verbally assauhive in response to little or no provocation (Monroe, 1978).

Moreover, this disorder has been described in both adults (Maletzlq, 1973; Monroe, 1978) and children

(Nunn, 1986), lending credence to the idea that the same neural substrate underlies defensive-rage-like

aggression over the course of brain development. Notably, this form of aggression is linked to structures

associated with the limbic-hypothalamic-midbrain-periaqueductal-gray (PAG) axis in humans (Monroe,

1985; Reeves and Plum, 1969; Grinker and Serota, 1938; Grinker, 1939; Alpers, 1940, Wortis and

Maurer, 1941). Because the explosiveness of behavior, marked sympatho-adrenal arousal, and ease of

provocation in these disorders also occur in defensive rage behavior in the cat, it is our belief that this cat

behavior is an appropriate model for study of the human disorders. Although fewer clinical studies have

considered predatory forms of aggressive behavior, we likewise believe that it, too, is an appropriate

model for study in the laboratory because it has been clearly identified in human studies (Vitiello et al.,

1990).


2. RESEARCH METEODf$

95

During the past 15 years, our laboratory has attempted to develop an understanding of the

neurochemicat basis of aggression and rage in the domestic cat. The initial stages of our research

program focused upon the modulatory properties of different limbic structures upon aggression and rage

(see Siegel and Brutus, 1990 ; Siegel and Pott, 1988 ; and Siegel et al., 1999, for a summary of these

Emlhtgs). These studies utilii brain stimulation, experimental lesions, and anatomical tracing methods

to identify those structures which potentiated aggression and rage, and those which suppressed those

behaviors. They further delineated the likely circuits within the forebrain by which such modulation was

mediated. These findings are summarized in Table 1.

The authors have focused on three brain areas-- the PAG, hypothalamus, and amygdala-- whose basic

anatomical relationships are shown in Fig. 1. Our research has focused on small-molecule

neurotransmitters such as excitatory ammo acids (PAAs), GABA, and the biogenic amines; as well as

neuropeptides such as opioid peptides, cholecystokinin (CCK) and neurokinins. A summary of these

Snclmgs and those from other laboratories can be found in by Siegel et al., (1999); and Siegel and Pott

(1988).

PREDATORY ATTACK

DEFENSIVE

R&WE

Fig 1. Major pathways for predatory attack (left) and defensive rage (right). AMY, amygdala; LH, lateral hypothalamus; MH, medial hypothalamus; PAG, periaqueductal gray of the midbrain.


Table 1.

Effects of Electrical Stimulation of Selected Brain Areas on Two Forms of Aggression.

Effect of Stimulation on

Defens- Preda- Major Afferents Major Efferents ive Rage tory

Attack Amygdahc Anterior + Amygdala: Central + Lateral hypothalamus,

PAG, tegmentum, BNST

Amygdala: Cortical, + Anterior medial medial, and basomedial hypothalamus, BNST Amygdala: Lateral and - + Substantia innominata basolateral Hippocampus: Dorsal _ Entorhinal cortex, Lateral septai area,

septal nuclei hypothalamus Hippocampus: ventral + Entorhinal cortex, Lateral septal area,

septal nuclei hypothalamus Septal nuclei: + Hippocampus Hippocampus, Ventrolateral hypothalamus, dBB Septal nuclei: AU other + Hippocampus =ppo=mpus, parts hypothalamus, dBB Bed nucleus of the stria + _ Substantia innominata terminalis (BNST) Subst innom: Medial _ BNST, n. accumbens Lateral hypothalamus Subst innom: Lateral + BNST, n. accumbens Lateral hypothalamus Cortex: prefrontal _ _ Mediodorsal thalamic n. Cortex: Ant. cingulate _ Mediodorsal thalamic n. cortex: Pyriform + _ Anterior hypo., BNST,

ventral hippocampus,

stria terminalis Hypothalamus: Medial + Amygdala, septal PAG, midline thalamus

nuclei, PAG, BNST Hypothalamus: Lateral - + Midline thalamus Tegmentum, BNST, and perifomical lateral septal area,

trigeminal motor nucleus, VTA

PAG: Dorsal + Hypothalamus, Trigeminal nucleus, amygdala hypo., locus ceruleus

PAG: Ventral + Hypothalamus Hypothahunus Diagonal band of Broca Lateral septal area Lateral hypothalamus,

hippocampus, amygdala Thalamus: Mediodorsai Prefrontal cortex, Midline thalamus nucleus anterior cingulate

cortex Thalamus: Midline _ Mediodorsal nucleus Lateral hypothalamus nuclei of the thalamus

Abbreviations: BNST, bed nucleus of the stria terminalis; dBB, diagonal band of Broca; n., nucleus; PAG, periaqueductal gray; VTA, ventral tegmental area; subst innom, substantia innominata.

Neural substrates of aggression in cats 97

2.1. Two Forms of msive Behavior

What cat owner has not witnessed his pet arching its back and hissing when provoked by a noxious

stimulus like a strange cat or dog, or been the dismayed recipient of a small animal delivered to him by the

cat? These behaviors are examples of the two forms of behavior we study, defensive rage and predatory

attack, which are oflen observed as spontaneously-occurring behaviors in many environments (Fig. 2).

Defensive rage is one response we study. Characteristics of this response include pronounced

sympathetic and behavioral signs such as growling, meowing, yowling, hissing, pupillary dilatation,

increased heart rate and blood pressure, urination, piloerection, arching of the back, and an aggressive

paw strike at an object moving through the eat’s visual field. In natural conditions, such behavior is

directed against an animal of the same or different species, often expressed when the cat, its territory, or

its kittens are threatened. Hissing, in particular, is a threat behavior and is also used in maintenance of

social dominance hierarchies. In our laboratory, defensive rage is produced by electrical stimulation of

the ventromedial or anterior medial hypothalamus or PAG. In our experiments, the threshold electrical

current (in mA) required to produce hissing, or, alternatively, the latency of the hiss response at a fixed

level of electrical unrent, are used as measures of the hissing response, and as measures of the intensity of

the stimulation-induced aggressive behavior.

The second form of aggressive behavior which is produced by electrical stimulation is predatory attack.

In the laboratory, it is remarkable to observe: an otherwise placid, inoffensiveseeming cat (we do not use

cats which are “natural tatters”) will be sitting or lying in the experimental cage with an anesthetized rat,

sometimes even using that rat as a pillow. However, upon stimulation, the cat will suddenly look up,

becoming alert, then stealthily circle and attack the rat with a well-directed bite aimed at the rat’s neck. If

stimulation is continued, the eat will repeatedly bite the rat, or it may pick the rat up by the skin and shake

it. Unlike defensive rage behavior, overt sympathetic signs characteristic of defensive rage are absent,

aside from some mild QUQihy dilatation. Predatory attack may be produced by stimulation of the lateral

or perifomical hypothalamus, and a stereotyped form of this behavior may also be elicited by stimulation

of the ventral PAG. Again, threshold and latency are used as dependent measures. The first report of this

behavior elicited by lateral hypothalamic stimulation was by Flynn and coworkers (Wasman and Flynn,

1962). In a related study, it was found that stimulated cats preferred to attack live or stuffed rats, rather

than a Styrofoam block or foam rubber block, when given a choice (Levison and Flynn, 1965), confirming

that the attack involves highly sensory discriminative processes. Such behavior is remarkable because of

the great degree of coordiiated, visually-die&d behavior which results from electrical stimulation of

such a small brain area not usually thought to be associated with such complex behaviors.


Fig 2. Photographs of cats engaged in defensive rage (top) or predatory attack (bottom) responses elicited by electrical stimulation of the medial and lateral hypothalamus, respectively (courtesy of Allan Siegel.)

2.2. Advantaees of the Cat as a Model

Si features make the cat uniquely suited as an experimental subject for exploring the neural basis of

aggression. First, the cat expresses two distinct and easily-measured forms of aggression which can be

elicited by electrical stimulation of different neural structures. Because our studies utilize two separate

behaviors, we can easily control for the behavioral specificity of our experimental manipulations (lesions,

stimulation, seizures, and drug administration). Such controls are extremely. A case in point: ifthe results

of one of our experiments indicate that a particular drug suppresses defensive rage behavior in the cat,


then that drug can later be tested against predatory attack behavior in order to determine whether the

suppressive effect is specific to defensive aggression or extends to all behaviors. Second, the responses

elicited by brain stimulation closely mimic aggressive behavior exhibited by felines under natural

environmental conditions and bear marked similarities to human aggression, as discussed above. Third,

due to the large size of the cat’s brain, it is possible to accurately implant multiple electrodes and canmdas

into diierent brain areas, which allows us to study the interactions among different brain structures using

the methods of electrical stimulation and injection of pharmacological agents. Fourth, we can quantify

these responses by measuring latency or current thresholds. Fifth, responses can be elicited easily and

repeatedly over a given experimental session, thus permitting systematic examination of how they can be

modiied by physiological or pharmacological challenge to the animal, or by changes in environmental

conditions. Because the predatory attack and defensive rage responses are stable over time, these

preparations may be used to study the long-term effects of such manipulations as lesions, experimentally-

induced epilepsy, or drug treatment. Sixth, cats are generally docile and easy to handle, in contrast to

primates.

2.3. Stimulation Techniaues

Stereotaxic surgery under aseptic conditions is employed to implant stainless steel “guide tubes” of

approximately 10 mm length and 1 mm diameter on the skull overlying the hypothalamus, PAG, and

limbic structures. After the cat recovers from surgery, a monopolar stimulating electrode or cannula-

electrode (for later microinjection of drugs) is lowered through a guide tube while the cat is awake and

freely-moving, and cemented into place at a location at which electrical stimulation produces the desired

defensive rage or predatoty attack response. Stimulation consists of repeated square-wave biphasic

pulses of 1 ms duration per half-cycle, at 63 Hz and 0.1 to 1 .O mA, which is continued until a response is

elicited or until 15 seconds have expired.

The following procedure is used for behavioral testing. First, the attack response is elicited by

stimulation of the hypothalamus of PAG and response thresholds or latency are recorded. Then, a drug is

injected either systemically or into a selected brain structure, and threshold or latency is again measured to

determine the effects of drug administration upon the attack response (see Fig. 3 for schematic diagram).

JJual-stimulation experiments are an elaboration of this basic technique, in which not one, but two

electrodes are used to stimulate two discrete regions of the brain. One electrode is placed at a site from

which an aggressive response can be elicited by stimulation, and the second electrode is placed at a site

which, when stimulated at the same time, either enhances or suppresses that aggression, aa measured by

the length of time (latency) that the cat takes to perform the aggressive behavior after stimulation onset.


STIMULATING ELECTRODE o CANNULA

ELECTRODE

Fig 3. The paradigm for a typical experiment involving the microinjection of pharmacological agents into specific brain structures is shown. A stimulating electrode for the elicitation of defensive rage behavior is located in the medial hypothalamus (MH); tip of cannula-electrode is located in PAG for injection of substances into that structure.

By using this dual-stimulation method, concurrent dual stimulation can be used to determine whether a

given brain site can facilitate or suppress a specific form of aggression, as determined by changes in

latency for response elicitation. In addition, dual-stimulation methods combined with microinjection

techniques can also be used to determine the receptor-neurotransmitter properties of the pathway

modulating a given form of aggression (see discussion below).

3. NEUROANATOMICAL SUBSTRATES OF DEFENSIVE RAGE AND PREDATORY

AGGRESSIOR

3.1. Defensive Ragq

Our laboratory has explored the neuroanatomical substrates of defensive in some detail. The overall

model which we have developed over the years is as follows. Specific “defensive rage neurons” exist

within the PAG and medial hypothalamus, which are necessary for the integrated expression of defensive

rage. These neurons contain many different receptors, such as NMDA S-HI’, and NE-1 receptors. When

defensive rage neurons in the PAG are activated, they excite neurons in the brainstem and spinal cord

which cause the autonomic and motor aspects of defensive rage. When defensive rage neurons in the


medial hypothalamus are activated, they excite PAG defensive rage neurons. We refer to this pathway

from medial hypothalamus to PAG as the pathway that e defensive rage. Additionally, specific

g&,&&8y neurons exist in the amygdala, bed nucleus of the stria terminahs, lateral hypothalamus, and

other structures, which synapse on these defensive rage neurons, thus modulating their activity and

modulating the intensity of the response. Lesions of the PAG can completely eliminate the stimulation-

induced aggressive response. However, lesions of modulatory structures do not eliminate the response.

In the future, it might become possible to distinguish defensive rage neurons from other neurons, based on

their neurochemical, electrophysiological, or morphological characteristics. -

Fig 4. Sites from which defensive rage (gray), predatory attack (stripes) or flight (black) can be elicited. Behavior can be evoked bilaterally; sites are shown unilaterally in the illustration for clarity. From Siegel and Pott, 1988, with permission.

3.1.1. I&p~Q~alamus. Defensive rage can typically be elicited by electrical stimulation of sites within

the rostro-caudal extent of the medial hypothalamus (Fig. 4). The structures contained within this region

include the ventromedial m&us, anterior nucleus, and medial preoptic region (Siegel and Brutus, 1990).

A central question is, namely, what neuroanatomical circuitry is utilii in the expression of defensive

rage behavior elicited from the medial hypothalamus? To answer this question, a series of functional

neuroanatomical studies was undertaken in our laboratory. In the 6rst set of studies, Fuchs et al.,

(1985ab) utili autoradiographic procedures to ident@ the descending pathways Corn the medial

hypothalamus that mediite defensive rage. The strategy employed for these studies was as follows: in

one approach, the anterograde tracer, tritiated leucine, was microinjected into sites in the medial

hypothalamus from which defensive rage had been elicited. Tritiated leucine is incorporated into proteins


within the cell body and transported down the axon to its terminal. In this manner, it is possible to trace

the label from the site of the injection (at an attack site) to the axon terminals. The animal is then

sacrificed and the brain tissue is processed by standard autoradiographic methods. The second approach

utilized 14C-2-deoxyglucose (2-DG) autoradiography, in which 2-DG is injected systemically and

defensive rage is elicited multiple times over a 60-minute period, afler which the animal is sacrificed, the

brain sections are used to expose x-ray film for 3-6 weeks, and then the film is developed.

The results obtained using these combined methodologies showed that the primary source of

hypothalamic e.fIerent fibers which project to the PAG in association with defensive rage, is not the

ventromedial nucleus, but the anterior medial hypothalamus. The principal projection of the ventromedial

nucleus which mediates defensive rage behavior is directed to the anteromedial hypothalamus. This

discovery was important because it shows that the neurons mediating defensive rage do not project

directly to the PAG. Instead, they project to the anterior medial hypothalamus, which itself projects to

the PAG. The VMH does project to the PAG (PfaEand Sakuma, 1982), but these projections appear not

to mediate defensive rage. It is of interest to note that the anterior medial hypothalamus also receives

major inputs from limbic structures such as the amygdala (Shaikh et al., 1993; Krettek and Price, 1978)

and septal area (Stoddard-Apter and MacDonnell, 1980; Brutus et al., 1984). These findings thus suggest

that the anterior medial hypothalamus is a principal site where modulation of defensive rage behavior

takes place (Pigs. 5,6.)

3.1.2. PAG. Defensive rage can be elicited from sites within the rostral half and dorsolateral part of

the PAG (Pig. 7; Siegel and Brutus, 1990). Utilizing procedures similar to those described above for the

study of the hypothalamus, a study was conducted to identify the efferent pathways of the PAG. The

principal descending fibers supplied motor and sensory trigeminal nuclei (presumably to mediate the jaw-

opening part of the hiss response), and the pontine tegmentum, including the locus ceruleus (for

sympathetic activation; Shaikh et al., 1987). Other investigations have also identified projections to the

solitary nucleus (nucleus tractus solitarius; Li et al., 1992); these projections may also serve as a substrate

for modulation of autonomic fimctions since the solitary nucleus projects to the ventrolateral medulla,

which in turn projects to the intermediolateral cell column of thoraco-lumbar spinal cord, and the solitary

nucleus is known to regulate cardiovascular fbnctioning (Ciiello and Calaresu, 1980) as well as making

reciprocal connections with limbic structures such as the hypothalamus, bed nucleus of the stria terminals

(BNST), and amygdala (Ciriello and Calaresu, 1980; Schacter and Saper, 1998; Kicardo and Koh, 1978;

Li et al., 1990). In addition, the PAG also projects rostrally to the posteromedial hypothalamus (Shaikh

et al, 1987; Li et al., 1991). This reciprocal connection may serve as a positive feedback mechanism by

which defensive rage can persist over expanded periods of time.


Fig 5. Anatomical diagram indicates that neurons at a&ctive defense (defensive rage) sites in ventromedial hypothalamus project rostrally to anterior medial hypothalamus. Anterior medial hypothalamic defensive rage neurons project caudally to the central gray (periaqueductal gray and ventral tegmentum). Modified, Corn Siegel and Pott, 1988, with permission.

The similarity of the pathways in the cat to those in the human is largely unlmown. However, clinical

correlations suggest that human patients with tumors or damage to various parts of the hypothalamic-

PAG axis experience changes in aggressive behavior (Monroe, 1985; Reeves and Plum, 1969; Grinker

and &rota, 1938; Alpers, 1940; Wortis and Maurer, 1941).

3.2. Predators Behavior

The sites from which predatory attack is most commonly elicited by electrical stimulation are located in

the perifornicsl lateral hypothalamus (Fig. 4; Siegel and BN~US, 1990). The ascending and descending


63 MN

0 PAG

Fig 6. Schematic circuit diagram indicating the flow of information from the ventromedial hypothalamus (VMN), through the anterior medii hypothalamus (AMH), to the periaqueductal gray (PAG).

projections of these attack sites are somewhat diise (Fuchs et al., 1981). Fibers descending from the

hypothalam~ project to the trigeminal motor nucleus, locus ceruleus, ventral half of the PAG, and

tegmental fields of the midbrain and pons, as well as to the ventral tegmental area (Chi and Flynn, 1971;

Smith and Flynn, 1980; Schoel et al., 1981; Fuchs et al., 1981). Electrophysiological studies suggest that

monosynaptic projections from the hypothalamus to the midbrain tegmentum are likely linked to

predatory attack (Huang and Flynn, 1975; Edmger et al., 1977; Sutin et al., 1975). Fibers descending

from the ventral tegmentum appear to synapse in the nuclei of the trigeminal and facial nerves as well as

the tegmentum of the lower pons (Chi et al., 1976). Studies utilizing electrical or chemical (homocysteic

acid) stimulation have provided evidence that the key area of the midbrain mediating predatory attack is


6.0

Fig 7. Within the PAG, defensive rage can be elicited most readily from sites in the dorsolateral part (gray area). A form of predatory attack is elicited from ventrolateral PAG (striped area), and flight is elicited from the dorsal aspect (black area).


the rostra-ventral PAG, since such stimulation of this region can elicit this form of aggression (Fig. 7;

Shaikh et al., 1987). There are also ascending fibers associated with predatory attack elicited by PAG

stimulation; they project to the lateral hypothalamus (Shaikh et al., 1987).

3.3. Modulator-v Pathm

As we have noted above, the principal modulation of aggression and rage is manifested by the limbic

system. Of the limbic structures studied, the amygdala plays a key role. This conclusion is derived from

studies of human patients with amygdaloid tumors or epileptic foci present in the amygdala (Falconer,

1973), as well ss experimental animal studies where lesions or brain stimulation were selectively applied

(Kluver and Bucy, 1939; Bard and Mountcastle, 1948; Egger and Flynn, 1967; Stoddard-Apter and

MacDonnell, 1980, Block et al., 1980). The discussion below describes our analysis of the behavioral

neurochemical mechanisms and anatomical substrates that underlie amygdaloid regulation of aggression

and rage.

3.3.1. The Amvn&Jg. The amygdala is a collection of nuclei situated deep in the rostral part of the

temporal lobe of the telencephalon. It receives inputs from many cortical areas (Henog and Van Hoesen,

1976), the medial geniculate nucleus of the thalamus (Ledoux et al., 1985), and solitary nucleus and the

parabrachial nucleus of the brainstem (Schacter and Saper, 1998). Its efferent fibers project mainly to the

hypothalamus, PAG, and prefrontal cortex (Krettek and Price, 1974, 1978; Bacon et al., 1996; Brutus et

al., 1986; Garcia et al., 1999; Llamas et al., 1977). Thus it is in a prime position to receive and integrate

information about sensory, visceral, autonomic, interoceptive, cognitive, and emotional processes, and

then to cause a change in the animal’s emotional behavior which is mediated through the hypothalamus

and PAG. In order to investigate the functions of these regions of the amygdala, a number of experiments

were carried out.

In a typical experiment. cats were prepared with guide tubes implanted on the skull dorsal to the

hypothalamus and amygdala. As noted above, electrodes were implanted into the hypothalamus flom

which defensive rage of predatory attack could be elicited, and into amygdaloid sites from which

modulation of aggression or rage could be generated.

Using this general paradigm, it was discovered that stimulation of the medial and cortical nuclei, as well

as the medial aspect of the basal nuclear complex facilitated defasive rage and suppressed predatory

attack (Brutus et al., 1986). Fibers in these areas project through the stria terminalis to the anterior


medial hypothalamus and BNST (Krettek and Price, 1978; Stoddard-Apter and MacDonnell, 1980; Siegel

and Brutus, 1990; Brutus et al., 1986). Conversely, fibers arising from the central, lateral, and lateral part

of the basal nuclear complex project through the ventral amygdalofhgal pathway (Siegel and Brutus 1990)

and suppress defensive rage and facilitate predatory attack. These fibers project to the substantia

innominata, lateral hypothalamus, and brainstem tegmentum (Hopkins and Holstege, 1978; Krettek and

Price, 1978; Siegel and Brutuq 1990).

3.3.2. Other Retions of the Limbic System. As we previously indicated, the bippocampal formation,

septal area, prefrontal cortex, and anterior cingulate gyrus modulate feline aggression (Table 2). In brief,

the likely anatomical substrates by which these liibic structures modulate aggression are as follows: (1)

the hippocampal formation utilizes a disynaptic projection to the hypothalamus- the first limb includes the

projection via the precommissural fomix to the septal area and the second limb includes a projection from

the septal area to the medial (Stoddard-Apter & MacDonnell, 1980) and perifomical hypothalamus

(Brutus et al., 1984); (2) the anterior cingulate gyrus and prefrontal cortex also can influence the

hypothalamus indirectly through a multisynaptic pathway- the circuit involves initial projections from

these cortical regions to the mediodorsal thalamic nucleus. From the mediodorsal nucleus, fibers project

rostrally through the midline thalamus to the nucleus reuniens. Fibers arising from the nucleus reuniens

then project to the perifomical hypothalamus (Table 2; Siegel et al., 1973a,b,c; 1977a,b).

In passing, it may be noted that the BNST is increasingly becoming the focus of research as part of the

“extended amygdala” (McDonald et al., 1999; Cassell et al., 1999) and has been implicated in fimctions as

diverse as anxiety (Davis and Shi 2000), aggression in rodents (Koolhaas et al., 1998), temperature

regulation (Pittman et al., 1998), stress (Herman and Cullinan, 1997; Gray et al., 1993), and reproductive

behavior (Swarm and Fiber, 1997; Pfaus and Heeb, 1997; Bialy and Kaczmarek, 1996), as well as

aggression in our feline model (Shaikh et al., 1986). Therefore, it is likely that a heuristic line of

investigation would be one in which the precise anatomical and fbnctional organization of this region is

delineated with respect to its role in aggression and rage.

In our research, we have identified neurotransmitter functions which may help to explain the effects of

drugs of abuse on aggression, as well as suggesting pharmacological targets for treatments of aggression.

This research is described below.


Table 2. Neurotransmitter Receptors, Aggression and Rage in the Cat.

Recevtor #nwture &@t of Rem&r Activation Commenr Pefcrences Defensive Rage Pm&tory Altack

Norepine- Activation of a2 receptors in Barrett et pkrine the anterior MH facilitates DR al., 1987, a2 MH Facilitation Not tested elicited from the VMH 1990 ar, 0 MH No efikct Not tested

Dopamine Activation of Dz receptors in Sweidan et D2 MH Facilitation Facilitation (IP) anterior MH facilitates DR al, 1990, Dr MH W,IC) Not tested elicited tiom VMH; systemic 1991;

No effect activation of 4 receptors shaikh et al., facilitates DR and PA 1991c

serotorlin Differential effects upon MB- Shaikh et al., 5-H-I-M PAG Suppression Not tested elicited DR follow activation 1997 s-HTJ s- PAG Facilitation Not tested of each of the receptor HTlC subtypes in PAG

GIYM NMDA receptors in PAG Luetal. NMDA PAG Facilitation Not tested mediate DR elicited from MH 1992; Non-NMDA PAG No effect Not tested and facilitation of DR from Schubert et

basal amygdala al., 1996a; Shaikh et al., 1994

GABA GABAr,

GAB43

PAG Suppression Not tested MH LH Suppression Not tested MH No effect Suppression LH No effect Not tested

Not tested Not tested

Reciprocal inhibition between Cheu et al., MH and LH is mediated 1997; through GAB& receptors in Shaikh and each of these regions; GABA, Siegel, receptor activation in P AG 1990; suppresses DR elicited from Schubert- either PAG or W Reilly et al.,

1997

Opioids Activation of p and 6 Shaikh et al.,

! PAG Suppression Not tested receptors suppresses defensive 1991a,b PAG Suppression Not tested rage; p receptor blockade in

K PAG No effect Not tested PAG eliminates CE suppression of PAG- elicited DR

CCK CCKEl CCK*

CC& receptor activation in Luo et al., PAG Facilitation Suppression PAG facilitates DR elicited 1998; PAG No effect Not tested from h4H and suppresses PA Sitthisom-

elicited fkom LH wong, 1998

Substance P SP NKr receptor activation in Han et al., NKI MH Facilitation Suppression MH mediates ME-induced 1996a;

facilitation of DR and Shaikh et al., suooression of PA elicited 1993

Abbreviations: CE, central nucleus of amygdala; DR defensive rage; LX, lateral hypothalamus; MB, medial hypothalamus; PA, predatory attack behavior; VhlH, ventromedial nucleus of hypothalamus.


4.1. Excitatorv Neurotransmitters

109

4.1.1. Bxcitatotv Amino Acids. The excitatory amino acids (BAAS), glutamate and aspartate, are

commonly thought to be the most widespread excitatory neurotransmitters in the central nervous system,

and their timctions are mediated by four types of receptors-- NMDA, AMPA kainate, and metabotropic

NMDA receptors are commonly thought to be involved in neural plasticity. Several studies conducted in

rodents provided evidence that the pathway from the medial hypothalamus to the PAG utilizes EAAs as a

neurotransmitter (Beart et al., 1988; Beart et al., 1990; Beitx, 1989).

It had been shown previously that microinjections of glutamate and D,L-homocysteic acid in the PAG in

the cat could elicit defensive rage (Bandler, 1984; Shaikh et al., 1987). These findings suggested to us

that excitatory amino acids may be released by medial hypothalamic neurons, which activate PAG neurons

to produce defensive rage in the cat. In order to firmly establish this conclusion, as well as to determine

which EAA receptor subtypes are relevant and to investigate other sources of EAA-containing neurons

projecting to the PAG, a series of experiments was csrried out.

Fist, it was shown that an EAA receptor antagonist blocked medial hypothalamic facilitation of PAG-

elicited defensive rage, and that NMDA injected into PAG defensive rage sites facilitated the rage

response elicited from that site (Pig. 8), thus supporting the view that medial hypothalamic neurons

facilitate defensive rage through the release of EAAs onto NMDA receptors in the PAG (Lu et al., 1992).

In this experiment, initially a cannula-electrode was implanted in the PAG of each cat which could evoke

defensive rage when electrical stimulation was supplied at that site. Then, using dual-stimulation

techniques, an electrode was lowered into a site in the medial hypothalamus which facilitated defensive

rage when current was applied to that site concurrently with stimulation of the PAG attack site.

Kynurenic acid, a nonspecific EAA antagonist, was microinjected through a cannula-electrode into the

PAG rage site and response latencies were again measured. It was found that drug administration

blocked the facilitator-y effects of dual stimulation of the medial hypothalamus-- i.e., dual stimulation no

longer facilitated the defensive rage over and above single stimulation of the PAG alone (Lu et al., 1992).

In the second phase of the study, we sought to determine which receptor subtype mediated this effect.

It was found that administration of an NMDA antagonist @P-7), but not an AMPA/kainate antagonist

(CNQX), into the PAG blocked medial hypothalamic facilitation of PAG-elicited defensive rage (Pig. 8).

Using a somewhat different paradigm, we also demonstrated that administration of AP-7 markedly

suppressed defensive rage elicited by single stimulation of the medial hypothalamus in a dose-dependent

manner (Schubert et al., 1996a; and unpublished observations). This provides further support that the

110

5-

-6 -

-17 -

-28 -

-39 -

T.R. Gregg and A. Siegel

- l.OrtM

----- 0.5nM

- O.lnM

.- - - Baseline

-50 ’ 0 1s so

POSTINJECTION TIME (YIN)

45

33

21

9

-3

-15

0 45 90 135 180

POSTINJECTION TIME (MN),

- 2nM AP7

----- .5nM AP7

- .lnM AP7

--- 4nM CNQX

--- Baseline

Fig 8. Top panel: microinjection of NMDA into PAG defensive rage sites produces a dose-dependent facilitation of defensive rage elicited from the PAG. Bottom panel: microinjection of the NMDA antagonist AP-7, but not the AMPAkainate antagonist CNQX, blocks medial hypothalamic facilitation of PAG-elicited defensive rage.


Fig 9. Glutamate-immunoreactive cells (filled circles), neurons retrogradely labeled with Fluoro-gold (open circles) and neurons double-labeled for both Fluorogold and glutamate (stars). Double-labeled neurons were located in the medial hypothalamus (n=S). Ch, optic chiasm; Cl, claustrum; Fx, fomix; HL, lateral hypothalamus; HP, posterior hypothalamus; HVM, ventromedial hypothalamus; OT, optic tract; RE, nucleus reuniens. From Schubert et al., 1996a, with permission.

putative glutamatergic projection from hypothalamus to PAG that mediates defensive rage does so by

acting on NMDA receptors rather than AMPA or kainate receptors. Additional support for this

hypothesis is given by the finding that infusion of NMDA into the PAG facilitated defensive rage elicited

by electrical stimulation of the PAG (Lu et al., 1992).

In the next phase of the study by Schubert et al. (1996a), retrograde (Fluorogold) labeling and

immunocytochemical techniques were employed to identify and characterize histochemically neurons in

the medial hypothalamus that project to defensive rage sites in the PAG. The results of this study

indicated that considerable quantities of glutamate neurons within the anteromedial hypothalamus project

to PAG defensive rage sites (Fig. 9). Schubert, et al., (1996a) ILrther supported the hypothesis that

NMDA receptors mediate the excitatory effects of this pathway by demonstrating by histochemical

methods that NMDA-RI receptors are present in the dorsolateral PAG at sites where defensive rage is

elicited.

In a separate study, we t%rther identified the presence of converging excitatory inputs into the PAG

from the basal amygdala whose functions are also mediated by NMDA receptors in the PAG. Evidence

for this phenomenon was provided by Shaikh et al. (1994). In this study, it was shown that facilitation of

PAG-elicited defensive rage elicited from the basal amygdala could be partially blocked by AP-7


microinjected into the PAG attack sites. Moreover, it was also demonstrated that basal amygdaloid

neurons projecting to PAG defensive rage sites (as shown with Fluorogold labeling) also stained

immunopositive for the neurotransmitter glutamate.

Thus, our evidence to date indicates that both the anterior medial hypothalamus and basal complex of

amygdala drive the excitatory mechanism within the PAG and these effects are mediated by NMDA

receptors. The importance of this evidence is apparent when considering a separate study by Schubert et

al. (1996b), in which it was demonstrated that NMDA receptors in the PAG mediate the facilitatory

effects of i.p.-administered ethanol on defensive rage behavior. In this study, it was found that

microinjection of the NMDA antagonist AP-7 into the PAG blocked the facilitatoty actions of ethanol on

defensive rage (Schubert et al., 1996b). This study marks the first localization of pro-aggressive effects

of ethanol to a particular brain area. The significance of this finding relates to its potential importance for

the treatment of human aggression since it is known that ethanol has been associated with enhanced

aggression in humans. A further interesting correlation involves the reported association of marijuana

intake with altered levels of aggression, and the presence of receptors for THC (cannabinoid or

anandamide receptors) in the PAG, as well as evidence that these receptors are li,mctional (Walker et al.,

1999; Vaughan et al., 2000; Tsou et al., 1998; Mailleux and Vanderhaeghen, 1992; Berrendero et al.,

1998; Romero et al., 1998).

4.1.2. Neurob. other peptides which have also recently been shown to potentiate defensive rage

include Substance P (SP) and cholecystokinin (CCK, see discussion below). The neuropeptide Substance

P is widely distributed in the brain, including the limbic system, but its functions in the central nervous

system are not well-understood, aside from mediation of nociception. Recent findings in our laboratory

point to an important role for it in aggression. It should be pointed out that there are three classes of

neurokinin receptors: NK-1, NK-2, and NK-3. It is more or less agreed that SP functions tend to be

mediated by NK-1 receptors, neurokinin A by NK-2 receptors, and neurokinin B by NIC-3 receptors

(Otsuka and Yoshioka, 1993).

Four lines of evidence suggested to us that it would be fruitlul to examine SP and NK-1 receptors in

connection with aggression. 1) The earliest suggestion that Substance P might be involved in aggression

was the tInding that SP and NK-1 receptors are widely distributed in brain areas involved in aggression

such as the amygdala, hypothalamus, and PAG, and other studies utilizing histochemical methods in

rodents discovered that SP-immunopositive neurons are present in the medial amygdala (Maeno et al.,

1993; Gtsuka and Yoskioka, 1993; Gallagher et al., 1992; Marchand et al., 1991, Quartsra and Maggi,

1998; Langevin and Emson, 1982; Warden and Young, 1988; Peterson and Shurlow, 1992). 2) The


medial amygdala is a region which, when stimulated, facilitates defensive rage and suppresses predatory

attack in the cat (Block et al., 1980; Stoddard-Apter and MacDonnell, 1980). 3) Substance P has an

excitatory action upon neurons (Mayer and MacLeod, 1979; Otsuka and Yoshioka, 1993; Otsuka and

Konishi, 1975; Wang and Robertson, 1998) and 4) it is present in axon terminals in the medial

hypothalamus (Shaikh et al., 1993). These facts suggested to us a testable hypothesis: that the facilitative

effects of the medial amygdala upon defensive rage are mediated through SP (N&l) receptors in the

medial hypothalamus.

Fig 10. Sites within hypothalamus from which defensive rage (filled circles) and predatory attack (open circles) were elicited by electrical stimulation. Also shown are the sites in the amygdala from which modulation of these responses was obtained by dual stimulation: fihed squares indicate facilitation of defensive rage; open squares indicate sites from which both facilitation of defensive rage and suppression of predatory attack were obtained. Abbreviations: AAA, anterior amygdaloid area; AR, basal nucleus of amygdala; AH, anterior hypothalamus; AL, lateral nucleus of the amygdala; AM, medial nucleus of the amygdala; CE, central nucleus of amygdala; Fx, fomix; HVM, ventromedial hypothalamic nucleus; OT, optic tract.(From Shaikh, et al., 1993, with permission).


2.5 nmolo

brrolino

0 5 60 120 150

POSTINJECTION TIME (YIN)

Fig 11. Microinjections of CP-96,345 into medial hypothalamic sites from which defensive rage can be elicited blocks facilitatory effects of medial amygdaloid stimulation. “Baseline” is the level of facilitation observed after dual stimulation of medial amygdala and hypothalamus before drug delivery. Negative values indicate facilitation of aggression. Error bars represent standard error of the mean for this and all subsequent figures.(From Shaikh, et al., 1993, with permission).

To investigate this hypothesis, we designed an experiment in which we first demonstrated that medial-

hypothalamically-elicited defensive rage is facilitated by dual stimulation involving the medial amygdala

(Fig. 10). Then, following microinjection of the NK-1 receptor antagonist CP-96,345 into the medial

hypothalamus, medial-amygdaloid-induced facilitation of defensive rage was blocked (Fig. 11). This

result was consistent with the hypothesis that the Substance P is the neurotransmitter released by medial

amygdaloid neurons onto medial hypothalamic neurons which mediate defensive rage and contain NK-1

receptors, the net effect of which is to potentiate defensive rage behavior.

Combined anatomical-immunocytochemical studies carried out at the same time established that 1) the

stria terminalis, the major pathway from the medial amygdala to the medial hypothalamus, contains dense

bundles of SP-positive axons, and 2) many medial amygdaloid neurons that project to medii

hypothalamic defensive rage sites stain immunopositive for Substance P (Fig 12; Shaikh et al., 1993).

In a related series of experiments, Han et al. (1996a) demonstrated that the medial-amygdaloid-induced

suppression of hypothahunically-elicited predatory attack is blocked by microinjection of the NK-1

antagonist CP-96,345 directly into the medial hypothalamus (Fig. 13), and that injection of the substance


Fig 12. A&r microinjection of Fluorogold into medial hypothalamus, Substance P-immunoreactive cells (filled circles), neurons retrogradely labeled with Phrorogold (open circles),and double-labeled neurons (stars) were located in the amygdala, BNST, and anterior medial hypothalamus. Abbreviations: AAA, anterior amygdaloid area; AB, basal nucleus of amygdala; AH, anterior hypothalamus; AL, lateral nucleus of the amygdala; AM, medial nucleus of the amygdala; BNST, bed nucleus of the stria terminalis; AC, central nucleus of amygdala; Fx, fomix; HIM, ventromedial hypothalamic nucleus; OT, optic tract.(From Shaikh et al., 1993, with permission).

P agonist Sar-9-Met-(02)l l-Substance P into the medial hypothalamus suppressed predatory attack (Fig.

14). This finding provided &her support for the presence of a Substance P pathway from the medial

amygdala to the medial hypothalamus. Han et al. (1996a) confirmed these findings with anatomical

evidence showing 1) Substance P was bound to receptors in the medial hypothalamus, as determined by

receptor autoradiography, suggesting the presence of NK-1 receptors in this region and 2) replication of

the anatomical-immunocytochemical study of Shaikh et al. (1993) which demonstrated that medial

amygdaloid neurons that were immunopositive for Substance P were also retrogradely labeled with

Fluorogold injected into the medial hypothalamus, thus showing that neurons projecting from the medial

nucleus of the amygdala to the medial hypothalamus likely contain Substance P (Han et al., 1996a). The

discovery that NIL1 receptors in the medial hypothalamus are involved in suppression of predatory attack

elicited from the lateral hypothalamus required that we postulate the existence of an inhibitory pathway


from the medial to lateral hypothalamus in order to account for this suppression. Discussion of the

intrahypothalamic inhibitory pathway is presented below.

Most recently, our laboratory has found that microinjections of GR73632, a NK-1 agonist, into the

PAG produced spontaneous hissing even when no electrical stimulation was applied to the PAG or

hypothalamus, in addition to facilitating defensive rage elicited from the medial hypothalamus (Fig. 15;

unpublished observations). The effect was so potent that one cat hissed more than 500 times in the hour

after injection and another cat hissed more than 50 times (unpublished data). Defensive-rage-lie

behavioral effects had only been obtained pharmacologically in the past by microinjections of glutamate or

homocysteic acid into the PAG (Bandler, 1984) or injections into the hypothalamus of the cholinergic

receptor agonist, carbachol (Baxter, 1968ab; Eckersdorf et al., 1987; Brudzynski, 198 1; Brudzynski et al.,

1995); the glycine receptor antagonist, strychnine (Masserman, 1936); or the GABA-A receptor

antagonists picrotoxin and pentylenetetrazol (Masserman, 1939, 1941).

--- 0.s nM

---- 0s nM

--- sdine

n -110; I 1 I J

8 5 50 120 lb0

FOST4NJECTION TIME (Mb) Fig 13. Microinjections of the NK-1 antagonist CP-96,345 block medial amygdaloid suppression of predatory attack behavior. Baseline is the percentage increase in response latency following dual stimulation whose value was then converted to zero. Following drug administration, medial amygdaloid stimulation suppressed predatory attack less. This is expressed as a negative percentage change. From Han et al. (1996a), with permission.


fza SP+ D SP+ Saline Bicucullinc

Fig 14. Microinjection of the NK-1 agonist Sar-9-Met-(02)11-Subs&e P-(SP + Saline, striped bars) suppressed predatory attack elicited from the lateral hypotbu&unus when it was injected into the medial hypothalamus. Pretreatment of the lateral hypothalamic predatory attack site with bicuculline (SP + bicuculline; solid bars) blocked this suppression. N= 5 cats. From Han et al., 1998, with permission.

The presence of GR73632-induced hissing reinforces the notion that NK-1 receptors may play a central

role in the expression of defensive rage. However, the specific nature of this effect remains poorly

understood.

4.1.3.. It has been shown that cholecystokinin (CCK) plays a role in anxiety (Vasar et

al., 1992; Koks et al., 2000; Aluoja et al., 1997). Our interest in CCK is based on the notion that the

behavioral and neural properties of anxiety and defensive rage may overlap. Accordingly, our laboratory

conducted a study to determine whether CCK compounds microinjected into the PAG could affect rage.

We observed that microinjections of the CCK-B receptor agonist pentagastrin into the PAG selectively

facilitated defensive rage behavior elicited by electrical stimulation of the medial hypothalamus. This

effect was due to activation of CCK-B receptors (Sitthisomwong, 1998). We tiher demonstrated that

pretreatment of the PAG with the selective CCK-B antagonist LY288513 suppressed defensive rage

elicited from the medial hypothalamus (Fig. 16, Luo et al., 1998). However, we have little understanding


F . . . . . . . . . . 200 pm01

-.,_ 4 nmol 8 nmol

J --- -------- I -I

I I I

we 5 30 60 180

TIME POSTdNJECTION (Min)

Fig 15. Microinjection of the NK-I receptor antagonist GR73632 into the PAG facilitated defensive rage elicited from medial hypothalamus in a dose- and time-dependent manner. All values were normalized to baseline (n=6 cats).

of the anatomical substrates or neural mechanisms by which CCK receptor activation regulates rage and

aggression.

4.1.4. Norepineuhrine. Amphetamines, which may be viewed as adrenergic agonists, are popularly

associated with violent behavior in humans, and this observation is borne out by some correlational data

(Smart et al., 1997, Richards et al., 1999, Szuster 1990). Recent data in monkeys have tended to show an

increase in aggression a&r amphetamine administration (Melega et al., 1997; Martin et al., 1990).

However, the data from placebo-controlled, short-term studies in humans and cats have been inconclusive

(Miczek and Tidey, 1989; Cherek et al., 1989; Zagrodzka and Jurkowski, 1988). In rats, one study

(Torda, 1976) found that foot-shock-induced aggression was facilitated by infUsion of a cocktail of

norepinephrine and dopamine into the medial hypothalamus, but another study (Geyer and Segal, 1974)

suggested that intraventricular infusions of norepinephrine reduced shock-induced aggression.

The studies described above suggest that activation of norepinephrine receptors in the brain areas

involved in aggression may alter aggressive responses. Experiments in our laboratory @arrett et al.,

1987, 1990) have shown that activation of alpha-2 adrenergic receptors in the anterior medial


w 17.0 nM

II 4.2 nY

m l.OSnM

cl Sallne

5 80 240

POSTlNJECTlON ‘IYYE (MN)

Fig 16. Microinjections of the CCK-B receptor antagonist, LY288513, into dorsal PAG defensive rage sites, blocked defensive rage elicited from the medial hypothalamus, in a dose- and time-dependent manner (n-7 cats). From Luo et al. (1998) with permission.

hypothalamus, but not alpha-l or beta receptors, facilitates stimulation-elicited defensive rage behavior

elicited from the ventromedial hypothalamus. This finding suggests that, in humans, aggression induced

by amphetamine abuse may be due mainly to alpha-2 adrenergic receptors, and so treatment efforts might

best be focused on alpha-2 antagonists (Pig. 21).

4.1.5. Dopamine. Three recent studies t?om our laboratory found that D2 receptor activation, but not

Dl receptor activation, facilitates both defensive rage and predatory attack (Shaikh et at., 1991c; Sweidan

et al., 1990, 1991). One site of action where D2 receptor activation facilitates defensive rage is the

anterior medial hypothalamus, where microinjections of the D2 agonist potentiate this response (Pig. 21;

Sweidan et al., 1991). It should be noted that two drugs that have recently shown promise in

ameliorating aggressive behavior in psychotic patients, clozapine and risperidone, have at least some D2

antagonist activity, but little, if any Dl activity (Glazer and Dickson 1998; Volavka, 1999; Buckley, 1999;


CE M BAS

+ EM/SP?

Fig 17. Proposed organization of the pathways from amygdala which modulate defensive rage. Excitatory pathways (+) corn the amygdala arise from the medial (M) and basai (BAS) nuclei. The medii nucleus projects to the medial hypothalamus (MH), using Substance P (SP) as a neurotransmitter; the basal nucleus projects to the PAG (CG), using glutamate (GLU) and possibly SP as a neurotransmitter. In contrast, there are two inhibitory pathways (-). One arises from the central nucleus (CE) and projects to the PAG, utilizing enkephalin @NK) as a neurotransmitter. The other is the reciprocal projection between MH and the lateral hypothalamus (LB). Also note that, as demonstrated by Lu et al. (1992), the projection from medial hypothalamic defensive rage sites to those in the PAG drives the attack mechanism by utilizing GLU as a neurotransmitter. Modified from Siegel et ai., 1999, with permission.

de Deyn et al., 1999; de Deyn and Katz 2000; Czobor et ai., 1995; Fmdling et al., 2000; Buitelaar 2000;

Katz et al., 1999; Spivak et al., 1998); and that the neuroleptic chlorpromizine, a dopamine antagonist,

also suppresses defensive rage in cats (Baxter 1968b; Maeda 1976). Thus D2 receptors may be an

appropriate target for development of drugs to ameliorate aggression. However, it should be noted that

that two of clozapine’s metabolites are S-HT2C antagonists (Baldesti et al.,, 1993; Kuoppamaki et al.,

1993).

. . 4.2.1. Omotd P@&g. Various researchers have reported the effects of administration of opioid

compounds on aggression in diierent species, which yielded varying and sometimes contradictory results

in severai species (Spiga et al., 1990, Berman et al., 1993; Haney and Miczek 1989; Kin&y and Bridges,

1986; Avis and Peeke, 1975). The most consistent finding was that withdrawal from morphine, or


- 50pmolJ.25ld

----- 25 pnolJ.26 ul

- 1opnoy.2sld

I 1 I I

5 00 120 loo

POSTdNJECTION TIME (Mb)

Fig 18. Microinjections of muscimol into the lateral hypothalamus suppressed predatory attack behavior elicited by stimulation of the lateral hypothalamus. Pm-injection latencies were converted to O?A and represent baseline values. Following drug delivery, response late&es increased, indicating a suppression of the response. This is indicated as a positive percentage change (n=S cats). From Han et al., 1996b, with permission.

administration of the nonspecific opiate antagonist naloxone, produced heightened aggression (Tidey and

Miczek, 1992ab; Yen-K00 et al., 1989; Suzuki et al., 1983; Malm et al., 1982; Stolerman et al., 1975) but

see Gianutsos et al. (1975).

Our laboratory first attempted to determine whether opiate receptor blockade by systemic

administration of the non-specific opioid antagonist, naloxone, could a%ct aggression and rage in the cat.

These initial experiments demonstrated that opioid receptor blockade with naloxone tircilitated defensive

rage and suppressed predatory attack (Brutus and Siegel 1989; Shaikh and Siegel 1989, Shaikh et al.,

1990).

In an effort to iden@ the neural substrates associated with opioidergic modulation of defensive rage,

we conducted several studies in which we microinjected the non-specific opioid agonist d-ala-

metenkephalinamide (DAME) into several limbic or limbic-related nuclei. These included the nucleus


acambens, BNST, and PAG. In general, microinjections of DAME into the PAG, BNST, and nucleus

accumbens suppressed defensive rage. (Shaikh et al., 1988; Shaikh et al., 1990; Brutus et al., 1988, 1989)

and, in each instance, the suppressive effects of DAME were blocked by pretreatment with naloxone,

providing further evidence in support of the specificity of action of opioid peptides upon aggression and

rage (see also Pott et al., 1987). In another experiment it was demonstrated that when such effects are

elicited by microinjections into the PAG, it is mu and delta receptors, but not kappa receptors, which are

involved (Shaikh et al., 1991a). Overall, these results fbrther suggest that opioid peptides modulate

aggression and rage by virtue of their effects upon neurons in these regions. It may be speculated that the

PAG, BNST, and nucleus accumbens may be the sites where systemically administered opiate drugs act to

affect aggression in humans, and that these structures may contain crucial synapses mediating the

aggression-heightening effects of opiate withdrawal.

Based upon these studies, we decided to focus upon a putative opioidqic projection from the central

nucleus of the amygdala to the PAG. In a previous experiment, it had been established that stimulation of

the central nucleus of the amygdala suppressed defensive rage elicited by electrical stimulation of the

hypothalamus (Brutus et al., 1986). thus it was reasonable to suspect that central nucleus stimulation

would have the same effect on aggression elicited from the PAG. Other investigators had provided

evidence that enkephalinergic neurons are situated in the central nucleus of the amygdala (Rae et al.,

1987; Uhl et al., 1978) and that the central nucleus projects to the PAG (Hopkins and Holstege, 1978;

Morrell et al., 1981; Price and Amaral, 1981). Therefore, in the following experiment (Shaikh et al.,

1991b), we tested the hypothesis that central-nucleus-induced suppression of defensive rage is mediated

via an enkephalinergic mechanism. Initially, dual stimulation procedures were employed in order to

demonstrate central nucleus suppression of defensive rage elicited from the PAG: Then, naloxone, or the

specific mu-opioid receptor antagonist beta-FNA, was microinjected into the PAG defensive rage site.

Both naloxone and beta-FNA blocked the suppressive effects of central nucleus stimulation in a dose

dependent manner. In a final aspect of the study, Pluorogold was microinjected into the PAG rage site

and the brain tissue was later processed for enkephalin labeling. The results demonstrated the presence of

enkephalin-positive neurons in the central nucleus which projected to the PAG. Collectively, these

experiments provided evidence that amygdaloid-induced suppression of defensive rage behavior is

mediated by enkephalinergic neurons situated in the central nucleus which project to the PAG and which

act upon mu-opioid receptors within the neuropil of the PAG (Fig. 17).


- aummusw

---- aomlrysld

- aelcmduslll

---- -

Fig 19. Suppression of predatory attack by stimulation of the media! amygdala was blocked by microinjection of the GABA antagonist bicucu!!me into the latera! hypothalamus. The pre-injection baseline response latency is represented by zero. (From Han et a!., 1996b, with permission).

4.2.2. The Role of GABAergic Neurons and ReceDtors in the Hwothalamus: ReciDroca! Inhibition

vgHwothalamus. We have found over the years that drugs and experimental manipulations

which faci!itate one form of aggression will tend to suppress the other. For example, electrical stimulation

of a site in the media! amygdala wi!! facilitate defensive rage and suppress predatory attack. The

discussion given below describes our recent work which discovered a likely underlying neural basis for

this e&ct.

Several experiments were conducted to investigate the role of GABAergic neurons in the hypothalamus

in regulating rage and aggression. In one study, Han, et a!. (1996b) characterized how GARAergic

neurons in the media! hypothalamus contributed to media! amygdaloid suppression of predatory attack.

As we noted above, Han, et a!., first demonstrated that media! amygdaloid stimulation suppressed

predatory attack elicited f?om the latera! hypothalamus. Then, it was shown that microinjections of the

GABA agonist, muscimo!, into the lateral hypothalamus, suppressed predatory attack elicited from the

latera! hypothalamus, thus conf!rming the presence of functional GARA receptors there (Fig. 18). In

successive experiments, it was shown that electrical stimu!ation of the media! hypothalamus or chemical


4 NK, RECEPTOR

Defensive

Fig 20. NK-1 receptors are present on both GABAergic and glutamatergic (GLUT) neurons in the medial hypothalamus (MEL). SP neurons from the medial amygdala (ME) project to MH and synapse upon GABAergic and glutamate@ neurons. GABAergic neurons from MH project to lateral hypothalamus (LH) and ghttamatergic neurons in MH project to the midbrain PAG. This, NK-I activation of GABAergic neurons in MH causes suppression of predatory attack behavior elicited from LH, while NK-1 activation of glutamatergic neurons in MH causes facilitation of defensive rage elicited from the MEL-PAG circuit. A disynaptic pathway is proposed to link the medial amygdala (ME) with the lateral hypothalamus (LH). The initial limb includes neurons from ME to the medial hypothalamus (MH). This excitatory pathway uses Substance P as a neurotransmitter. The second limb is comprised of projections from MH to LH. This pathway is believed to be inhibitory and GABAergic. “+“: excitation; “-“: inhibition. Modiied from Yao, et al., (1999) with permission.

stimulation of this region by microinjection with the substance P agonist (Sar-9-Met-(02)l I)-Substance P

also suppressed predatory attack elicited from the lateral hypothalamus and that these suppressive effects

were blocked following administration of the GABA antagonist bicuculline into the lateral hypothalamic

attack site (Pigs. 18 and 19), indicating that these t%nr.tions lvere mediated by GABA-A receptors in the

lateral hypothalamus. Further anatomical-immunocytochemical studies confhmed the presence of GABA

immunoreactivity in medial hypothalamic neurons which project to the lateral hypothalamus.


From this study, coupled with the study described above, by Shaikh et al. (1993) we have shown that

electrical stimulation of the medial amygdala facilitates medial-hypothalamically-elicited defensive rage

and suppresses lateral-hypothalamically-elicited predatory attack. These studies firther reveal that these

modulatory effects are mediated through SP-NK-1 receptors in the medial hypothalamus (Pig. 20). In a

most recent study, Yao et al. (1999) provided evidence that NK-1 receptors are situated on both

glutamate-containing and GABA-containing neurons in the medial hypothalamus (Fig. 20).

In light of the Sndiigs described above, we can now understand how the medial amygdala differentially

affects defensive rage and predatory attack. The circuit mediating facilitation of defensive rage includes

medial amygdaloid neurons that release Substance P onto medial hypothalamic glutamate@ neurons.

Activation of SP-NK-1 receptors situated on these medial hypothalamic glutamatergic neurons excites a

pathway that projects to the PAG. Collectively, this multisynaptic projection originating in the medial

amygdala drives the defensive rage mechanism (Schubert et al., 1996a; Lu et al., 1992). In a parallel

manner, the medial amygdala also activates GABAergic neurons in the medial hypothalamus via SP-NK-I

receptors. These GABAergic neurons then project to the lateral hypothalamic (predatory attack)

neurons, causing suppression of predatory attack (Pig. 20).

Utiliig a parallel analysis, Cheu and Siege! (1998) showed that lateral hypothalamic stimulation

suppressed defensive rage elicited from the medial hypothalamus and that this suppressive effect was

mediated by GABA-A receptors in the medial hypothalamus. This study additionally showed that

GABAergic neurons project to the medial hypothalamus from the lateral hypothalamus, thus revealing the

existence of reciprocal GABAergic pathways linking the medial and lateral hypothalamus (Fig. 17).

The implication from these studies is that defensive rage and predatory attack are mutually incompatible

responses; namely, when one form of aggression is prepotent, the other is suppressed. Such a mechanism

would have survival value for the animal in its natural environment, enabling the animal to engage the

appropriate responses and suppress an inappropriate response at times when simultaneous expression of

the two behaviors would be inimical to the animal’s survival. For example, a cat which displayed the

behaviors of affective defense (yowling, growling and hissing) would frighten away any prey that it was

trying to attack. Our studies have determined that predatory attack and defensive rage are mutually

incompatible responses in cats; however, research in humans suggests that human aggression may include

elements of both forms of aggression, though one form of aggression may be prepotent over the other.

Specifically, while defensive aggression in humans can often appear in a relatively pure form, predatory

aggression may be mixed with elements of defensive aggression (Vitiello and Staff, 1997, Vitiello et al.,

1990; Meloy, 1997).


42.3. Serotonin. Serotonin has long been implicated in the control of aggressive behavior. In general,

experimental manipulations which increase serotonin receptor activation have been found to decrease

aggression, and those which decrease receptor activation were found to increase aggression (reviewed in

Shaikh, et al, 1997; see also De almeida and Lucion, 1994). Previous reports had indicated that selective

destruction of serotonin (5-HT) neurons in the raphe complex of the cat (Romaniuk et al., 1987) or rat

(Pile and Deakin, 1980) or the rat hypothalamus (Vergnes et al., 1988) caused an increase in aggression.

Serotonin receptor activation in the amygdala or hypothalamus reduced aggression whereas receptor

blockade in these areas facilitated aggression (Golebiewski and Romaniuk, 1985; Rodgers, 1977).

Because axons and preterminals that were immunopositive for 5-HT were found in the dorsolateral PAG

of the cat (Shaikb et al., 1997), and the PAG presumably represents the most caudal region of the central

nervous system where integration of defensive rage takes place, we sought to determine the effects of

selective 5-HTlA receptor activation in the PAG upon defensive rage, using the agonist 8-OH-DPAT.

We demonstrated that microinjections of 8-OH-DPAT into the PAG suppressed hissing elicited from the

medial hypothalamus, and that this suppressive effect is blocked by pretreatment with the selective 5-

HTlA antagonist, p_MPPI (Kung et al 1994), thus indicating the selective suppressive action of 5-HTlA

receptors on PAG neurons mediating defensive rage (Pig. 21). A caveat to this conclusion is that 8-OH-

DPAT may also act on 5-HT7 and dopamine D2 receptors (Ying and Rusak 1997; Matuszewich et al.,

1999; Lejeune et al., 1997; DuPont et al., 1998; Duncan et al., 1999; Thomas et al., 1999), in which case,

it may also affect dopamine levels (Lot-rain et al., 1998), and thus somewhat complicate our interpretation

of the data.

Not ail 5-HT receptor subtypes suppress defensive rage. Administration of the 5HT2/1C receptor

agonist, DOI, was found to facilitate hissing when microinjected into the PAG (Shaikh et al., 1997). It

may be noted that DO1 acts as an agonist at S-HT2A, 5-HT2B, and 5-HT2C (also known as 5-HTlC)

receptors (Shannon et al., 1984; Porter et al., 1999; Loric et al., 1995; Choi et al., 1994). However, DO1

may also a&t dopamine levels (Yan, 2000).

These findings tend to support our working model of the neuronal mechanism of defensive rage. This

model states that specific “defensive rage neurons” exist within the PAG which express many different

receptors, such as NMDA, 5-HT, and NK-I receptors, and which, when activated, release

neurotransmitter onto neurons in the brainstem and spinal cord which generate the autonomic and motor

aspects of defensive rage. These findings support this model because it is known that 5-HTlA receptors

usually activate G-proteins of the inhibitory G, subtype (Raymond et al., 1999; Sim-Selley et al., 2000; but

see Albert et al., 1999), and that 5-HT2 receptors can act to enhance pre-existing depolarizations of


0 5-HT

Fig 21. Schematic diagram illustrates the relationship of the monoamines dopamine (DA), norepinepbrine (NE) and serotonin (MIT) within the defensive rage circuit. Norepinephrine and dopamine neurons project to all areas of the forebrain, including AMH, and release neurotransmitter at this site, driving the rage mechanism via alpha-2 adrenergic receptors (for NE) and dopamine D2 receptors respectively. Serotoninergic neurons also project widely to the forebrain and brainstem, including the PAG, and release serotonin at this site, exerting an inhibitory action upon neurons via 5-HTIA receptors.

neurons (Rahman et al., 1993ab, 1995). Thus, broadly speaking, it might be expected that MITlA

receptors are generally inhibitory and 5-HT2 receptors are generally excitatory. We would expect that

PAG defensive rage neurons might express both 5-HTlA receptors and 54IT2 receptors and that the

activation of 5-HTlA receptors with 8-OH-DPAT activates G proteins, thus decreasing the excitability

of these neurons and suppressing defensive rage, whereas DO1 activates 5-HT2 receptors, thus increasing

the excitability of the PAG defensive rage neurons and enhancing defensive rage. However, tinther

studies must be carried out in order to demonstrate this possibility.


5. Conclusionq

Our research has intensively investigated the neural stnztur~ in the hypothalamus and brainstem that

mediate aggression and rage, as well as those that modulate these forms of aggression. The most

important structures mediating aggression are the medial and lateral hypothalamus, PAG, and parts of the

brainstem tegmentum. The sttuctures modulating aggression, shown in Table 2, include the amygdala,

septal area, hippocampus, BNST, prefrontal cortex and anterior cingulate cortex. The authors have

begun to determine the neurochemical properties of several of the key circuits that mediate or modulate

aggression and rage. The most intensively-studied pathway in our laboratory has been the projection

from the anterior medial hypothalamus to the PAG. This pathway mediates the expression of defensive

rage. The transmitter in this pathway is glutamate, and acts through NMDA receptors in the dorsolateral

PAG. Perhaps the most potent region that modulates aggression and rage is the amygdala. Our studies

have revealed that the modulating effects of the amygdala upon aggression and rage are dependent upon

the subnucleus in question. Specifically, facilitation of defensive rage is mediated by both the medial

nucleus and parts of the basal complex. The medial nucleus facilitates defensive rage via a Substance P

pathway (i.e., the stria terminalis) projecting to the anterior medial hypothalamus that engages NK-I

receptors to excite a descending glutamatergic pathway to the PAG. Facilitation of defensive rage is

further achieved by the actions of a basal amygdaloid projection to the PAG that acts through NMDA

receptors. Power&l suppression of defensive rage is generated through an enkephalinergic projection

from the central nucleus to the PAG which is mediated through mu-opioid receptors in the PAG. Other

receptor mechanisms that play important roles in modulating defensive rage by acting on neurons include

NK-1 and CCK-B receptors, which facilitate defensive rage, and GABA-A and S-HTlA receptors whose

activation suppresses defensive rage.

Studies of catecholaminergic systems in the anterior hypothalamus have demonstrated that NE-alpha-2

receptors and dopamine D2 activation facilitates defmsive rage. Other studies have suggested that the

facilitatoty effects of dopsmine D2 receptors are not specific to defensive rage but affect predatory attack

in a similar manner.

Recent studies in our laboratory have revealed the presence of reciprocal GABAergic inhibitory

pathways between the medial and lateral hypothalamus. This pathway has survival value for the animal in

that it ensures that when one form of aggression is prepotent, the other form is inhibited. For example,

when predatory attack is prepotent, mechanisms related to the expression of defensive rage are

suppressed, guaranteeing that any vocalization detrimental to the surprise required in predation will be

suppressed.


We view this research as a preliminary step in delineating the neural circuits involved in aggression.

This approach will hopet%lly enable us to gain a greater understanding of the neural substrates and

mechanisms underlying human emotions and aggression. It is possible that our research may also offer

insights into the mechanisms underlying how antipsychotics, heroin, methamphetsmine, and ethanol affect

aggression, by identifying the neural structures and neurotransmitter-receptors upon which they act to

a&ct aggression and rage (namely, dopamine, opiate, norepinephrine, and NMDA receptors).

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