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

    mnted in the USA. Au lights reserved 027%5846/01/$-see front matter

    PII: 5027%5846(00)00150-0



    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)


    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 Alzheimers 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,

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