Pii: s0149-7634(98)00040-2

Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 Neuropharmacology of brain-stimulation-evoked aggression Allan Siegela,*, Thomas A.P. Roelingb, Thomas R. Gregga, Menno R. Krukc aDepartment of Neurosciences, New Jersey Medical School, Newark, NJ 07103, USA bDepartment of Anatomy and Embryology, Faculty of Medicine, University of Nijmegen, 6500 HB Nijmegen, The Netherlands cMedical Pharmacology, LACDR, Sylvius Laboratory, University of Leiden, 2333 AL Leiden, The Netherlands Received 1 May 1998; accepted 5 May 1998 Evidence is reviewed concerning the brain areas and neurotransmitters involved in aggressive behavior in the cat and rodent. In the cat, two distinct neural circuits involving the hypothalamus and PAG subserve two different kinds of aggression: defensive rage and predatory (quiet-biting) attack. The roles played by the neurotransmitters serotonin, GABA, glutamate, opioids, cholecystokinin, substance P, nore- pinephrine, dopamine, and acetylcholine in the modulation and expression of aggression are discussed. For the rat, a single area, largely coincident with the intermediate hypothalamic area, is crucial for the expression of attack; variations in the rat attack response in natural settings are due largely to environmental variables. Experimental evidence emphasizing the roles of serotonin and GABA in modulating hypothalamically evoked attack in the rat is discussed. It is concluded that signi®cant progress has been made concerning our knowledge of the circuitry underlying the neural basis of aggression. Although new and important insights have been made concerning neurotransmitter regulation of aggressive behavior, wide gaps in our knowledge remain. q 1999 Elsevier Science Ltd. All rights reserved.
Keywords: Aggression; Behavior; Attack; Limbic system; Rat; Cat; Neuroanatomy; Hypothalamus; PAG; Septal nuclei; Amygdala; Electrical stimulation; Neuropharmacology; Receptors; Neurotransmitters; Serotonin; Acetylcholine; Dopamine; Norepinephrine; Glutamate; GABA; Neuropeptides; Opioids; Cholecystokinin; Substance P; Agonist; Antagonist; Serenic; Psychotropic; Tranquilizer; Depressant; Electrical stimulation; Intracranial injection; Over the past three decades, a number of investigators In both cats and rats, aggression can be elicited by elec- have electrically stimulated discrete brain areas in order to trical stimulation of the hypothalamus and periaqueductal evoke aggressive behavior in several species, mostly in cats gray (PAG) of the midbrain, suggesting that aggression and rats [12, 25, 34, 56, 75, 76, 98, 115, 119, 120]. Such derives from similar neural substrates in both species models of aggression possess three particular strengths.
[119, 120, 147, 206, 207]. However, the responses in rats First, the responses closely resemble those that occur differ greatly from those in cats, in terms of the form of under natural conditions, particularly in the cat [126].
behavioral responses, speci®city of the neural substrate, Second, the responses can be repeatedly elicited over roles of speci®c neural structures (e.g. the PAG), involve- many trials in a reliable manner, with stable latencies and ment of neuroactive substances (e.g. serotonin and opioids), thresholds. Third, because the responses are stable, an and presumed function of the responses. Some of these objective standard is provided by which changes in response disparities may result from methodological limitations: can be evaluated by statistical analyses. Thus, one can detect since the cat has a larger brain and the dorsal surface of subtle response changes that occur due to the infusion of its skull is larger and sturdier than the rat's, complicated drugs, either systemically or centrally, or due to other techniques frequently used in catsÐsuch as infusing physiological or environmental manipulations. This allows drugs into a brain site and then electrically stimulating investigators to characterize the neural circuits that produce that site or another siteÐare only gradually becoming avail- aggression. The present review describes the behavioral and able for use in rats. By applying such techniques to the rat, neural properties of these models of aggression and surveys some of the apparent differences probably will disappear.
the literature concerning the roles of different putative However, since the cat and rat occupy different ecological neurotransmitter systems in the regulation of aggression.
nichesÐthe cat is a solitary, specialized carnivore, and the rat is a colony-dwelling, opportunistic omnivoreÐit is to be expected that different mechanisms have evolved to control * Corresponding author. Tel.: 1 1-973-972-4471; fax: 1 1-973-972- 5059; e-mail: [email protected].
aggression. By identifying the similarities and differences 0149-7634/99/$ - see front matter q 1999 Elsevier Science Ltd. All rights reserved.
A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 between these species in which aggression subserves differ- delivered to the attack site that can elicit the response, or ent social and ecological functions, it is hoped that the prin- alternatively as the current intensity eliciting the response in ciples underlying the neural control of mammalian 50% of the trials; (2) response latency, de®ned as the time aggressive behavior will be elucidated.
between onset of electrical stimulation and elicitation of the response at a ®xed current level.
1. Behavioral aspects of brain-stimulation elicited attack 1.2. Using response patterns to categorize aggression In ethology, both the releasing and directing stimuli and the speci®c spatio-temporal pattern of a behavior are used to 1.1. Categorization and measurement of aggression assess the motivational state'' of animals in natural There is a semantic difference between cat and rat models settings. It has been argued [112, 116] that since such of aggression. In the cat, one can categorize stimulation- motivational states'' are constructs derived from beha- induced aggression as affective defense or predatory attack.
vioral observations, they may not have a simple relationship In the rat, two types of motivational state in aggressive to the activity of a speci®c brain mechanism. Therefore, behavior, offense'' and defense'', have been postulated there is a risk in classifying behaviors obtained by electrical as categories [40, 112, 116, 218, 222]. These categories in stimulation of a speci®c area into such motivational rat and cat are based on different criteria. Affective defense systems''. It is evident that the response pattern under or defensive rage in the cat consists of threat postures, which natural conditions will be affected by other controlling may be followed by strikes upon provocation, similar to the mechanisms in addition to the one activated by stimulation.
natural defensive behavior of a cat towards intruders in a Therefore, it is essential to assess the factors (goal-object, territory or towards other threats to itself or its offspring; this stimulation intensity, behavior of the opponent) that deter- behavior resembles both offense'' and defense'' in the mine the spatio-temporal pattern of brain-stimulation- rat. However, in the rat, threat behavior (lateral threat), induced aggression. This issue is not without theoretical which is mainly displayed by the resident in territorial ®ght- impact. Many of the behavioral concepts currently used in ing (except in the few cases in which it is exhibited by the psychiatry and ethology are derived from the early in¯uen- intruder instead), is labeled offensive'' behavior in tial observations on brain-stimulation-evoked behavior in contrast to the defensive'' attack behavior of a weaker cats [96] and domestic fowl [225], made at a time when intruder reacting to attacks by other rats [38±41]. Thus, the disciplines of physiology and ethology were closer.
threat in defense of a territory in the cat has acquired the 1.3. Attack patterns in two feline models of aggression label defensive'', whereas in the rat it has generally elicited by electrical or chemical stimulation acquired the label offensive''.
In the cat, the distinction between defense and predation 1.3.1. Quiet biting attack behavior has been corroborated by neuroanatomical and pharmaco- Quiet biting attack behavior, which is predatory in nature, logical ®ndings [36, 55, 92, 93, 184, 197]. In contrast, in the is typically characterized by stalking'' of a prey object rat the distinction between offense'' and defense'' has such as an anesthetized rat, followed by the biting of the been made on the basis of a rather confusing mixture of back of its neck. The attack begins after onset of stimulation causation, function, form and the effect on the target of and usually persists until stimulation is terminated. On occa- the attack, not on the basis of neuroanatomical ®ndings; sion, the cat may also strike the rat with its forepaw prior to this distinction is not useful in understanding brain-stimula- biting it [74, 227]. This behavior is remarkably similar to the tion-induced aggression. For the ethological point of view, response that occurs under natural conditions where stalking see Ref. [218] for an excellent discussion of the problems and killing of a rat in the open ®eld is readily observed caused by such an approach. Recent evidence suggests that [126]. Predatory attack is de®ned as occurring when the in the rat, the neural substrate for stimulation-elicited cat bites the target.
aggression is a single, multipurpose mechanism, releasing attack whenever it is useful for survival, and that a single 1.3.2. Defensive rage behavior area, the hypothalamic aggressive area (HAA), underlies This form of aggressive behavior, originally described as both offensive'' and defensive'' aggression, the differ- affektive abwehr'' by Hess and Brugger [96], is character- ences between them being due to differences in environmen- ized by noticeable affective signs, including piloerection, tal variables (see below). We will refrain from attributing retraction of the ears, arching of the back, marked pupillary observations of behavior to motivational'' systems impli- dilatation, vocalization and unsheathing of the claws. The cated by observations in natural settings, and we will retain dependent variable often measured by experimenters is the the straightforward nomenclature of the cat literature.
time between stimulation onset and onset of the audible It should be noted that the two principal dependent vari- portion of the hiss response. This response typically ables used in these studies of aggression are: (1) response involves mouth opening, baring of the teeth, an upward threshold, de®ned either as the lowest electrical current curling of the edges of the tongue, and then a hiss.
A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 Fig. 1. (A) Distribution of sites within the preopticohypothalamus from which defensive rage (stippled area) and quiet biting attack (striped area) are most frequently elicited by electrical stimulation. Number in upper left-hand corner of ®gure indicates the frontal plane of section. (B) Distribution of sites within the PAG from which defensive rage and predatory attack can also be elicited by electrical or chemical stimulation. Note that, at the level of the hypothalamus, predatory attack sites are situated lateral to those associated with defensive rage and, at the level of the PAG, defensive rage sites are situated dorsal to predatory attack sites. Abbreviations: AH, anterior hypothalamus; F, fornix; IC, internal capsule; LH, lateral hypothalamus; MB, mammillary bodies; OT, optic tract; RE, nucleus reuniens; VM, ventromedial nucleus. (From Ref. [201] with permission.) Stimulation applied at medial hypothalamic sites from pharmacology of narrowly circumscribed brain areas. In which defensive rage can be elicited results in a dramatic contrast, in rats, a more broad, general picture arises activation of both sympatho-adrenal and cardiovascular from studies involving either infusion of a chemical into systems, producing marked increases in heart rate, blood the brain, with subsequent observation of the behavioral pressure, and peripheral epinephrine and norepinephrine outcome, or peripheral administration of the substance, levels [210].
followed by measurement of its effects on hypothalamic Following its original description, this response was attack. For example, recent work in stimulation-induced given the misnomer sham rage'' because it was viewed aggression in the cat focused upon the roles of opioid as a pure motor act devoid of forebrain involvement [140].
and excitatory amino acid receptors within the PAG.
We now know that the forebrain is typically involved: Such studies have not been carried out in the rat for two defensive rage responses can be directed at speci®c moving reasons. First, the cat is, at present, better suited than the objects such as an awake rat, cat, or even the hand of an rat for multiple brain manipulations. Second, in the rat the experimenter. This response is a very real one, and it has nonspeci®c opioid antagonist naloxone does not affect ethological signi®cance: a nearly identical response can be stimulation-induced attacks [112], and selective lesions of evoked under natural conditions [126]. For example, this the PAG only slightly and transiently affect hypothalamic response may occur when a cat is intimidated by a threaten- and territorial aggression [148]. Instead, in rats attention ing stimulus, when a cat perceives that her kittens are endan- has been paid to the role of serotonin receptors in the study gered by another animal, or when a cat's territory is of the effects of serenic'' drugs [112, 118, 157, 158, 219], invaded. The typical sites from which predatory attack as well as GABA, glutamate, and several other neurotrans- and defensive rage can be elicited by electrical stimulation mitters, as shown in Table 2.
are shown in Fig. 1.
1.4.1. Continuous diversity of hypothalamic attack patterns 1.4. Hypothalamic aggression in the rat: a different Attacks elicited by hypothalamic stimulation in the rat have been classi®ed into complete'' and incomplete'' attacks [108], and into affective'' and quiet attacks'' Different emphases are evident in the literature on [161±163], jump attacks'', bite attacks'' [231], attack feline and rodent aggression. In cats, emphasis has been jumps'', and clinch ®ghts'' [117, 120, 219]. Such distinc- placed on intensive study of the anatomy and behavioral tions are necessary to describe the diversity of the attacks, A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 but the typology actually covers a continuum of forms, with for survival. The form of the attack is determined by: (1) the many intermediate forms and transitions between them.
intensity of stimulation current; (2) directing stimuli from There is a general pattern in all attacks. Attack the opponent; (3) the tactics the opponent adopts to avoid patterns range in violence from mild biting of the neck being attacked, e.g. hiding the attack-directing stimuli from of an opponent through hard biting of the head and back, the attacker. Curiously, the exact position of the electrode through hard biting of the back accompanied by hind within the HAA has relatively little effect on the form of the paw kicks in the ¯ank, to clinch ®ghts and attack attack [119, 120].
jumps [115, 117, 119]. The bite is always present and First, at intensities below the threshold for attack, stimu- the front paws may be placed at the opponent's neck or lation makes the rat more self-directed and more sensitive to back as a concomitant for biting. Subsequently, the hind the activities of its partner. The partner reduces its physical paws may come into action to kick the ¯ank, chest or interactions with the stimulated rat. As stimulation intensity belly of the adversary. Attack jumps arise when the increases, the withdrawal of both rats from social interac- opponent goes into an upright position, presumably to tions also increases [90], but there are still no signs of protect its back from being bitten. In attack jumps, the aggression. At the approximate threshold intensity, the attacker jumps from some distance toward the opponent, mutual withdrawal from social interactions apparently using its hind paws for takeoff and tail for balance and fails and violent interactions take over, as bites directed at support. Upon landing, the attacker tries to bite the head, the back and neck of the partner are released. Further while delivering a forceful blow with the hind paws increases in the intensity of stimulation will shorten the against the opponent's chest or belly. In clinch-®ghts, latencies for attack and bias the attacks towards more the rats often become locked in an on-top/on-back posi- violent forms, accompanied by a tendency to use the hind tion. Clinch-®ghts occur when one of the rats loses its paws to kick at the body, in virtually all electrode place- footing following an attack jump, or when an opponent ments studied [114]. Increasing stimulation intensity seems fails to assume an upright defensive position. From bite to activate the attacker in cephalo-caudal order [113, 115, attack to clinch ®ght and attack jump, there is a general tendency to increase the arching of the back. The head Second, strong directing stimuli on the head and rostral and neck are the ®rst targets of attack followed by the part of the back of the opponent are apparently essential upper and lower back [115, 117, 147, 149]. Although a components in shaping the form of the attack [117].
dominant rat could easily bite the exposed ventral surface Third, the tactics of the opponent are important in deter- of a submissive rat lying on its back, this surface is mining the form of the attack, as mentioned above. Other rarely bitten, even in a clinch ®ght [117]. Rats ®ghting examples include the following. If the opponent freezes in a in natural settings bite the same targets [38±41, 149].
crouched position, a bite accompanied by a kick of the hind Hypothalamic attack can be directed against subordinate paws often develops into a clinch ®ght. The treatment of rats, dominant rats [108, 117], anesthetized rats, dead-and- opponents with a high dose of morphine in order to alleviate frozen rats [117] and mice [12, 105, 108, 161±163, 223, pain and anxiety, a procedure which is now routine, causes 231]. Male rats also attack receptive or unreceptive females them to stop emitting 22 kHz ultrasonic distress vocaliza- [108, 117, 173]. Female rats attack other females as well as tions and to stop adopting defensive upright positions.
males [114, 149]. In the absence of a rat-like object, attack Consequently, attack-jumps are abolished (Fig. 2) and does not occur. For example, rubber toys shaped like rats are only straight attacks on the back occur. If the stimulation not attacked [117]. Such ®ndings parallel the patterns is strong, such attacks are followed by a clinch. Neither observed in the cat, where stimulation-induced attack is latencies to attack nor the threshold current intensity are preferentially directed against live rats (as opposed to changed. These observations show that while the active dead or toy animals) [125].
participation of the opponent is not required to elicit an Different strains of rats have different hypothalamic attack, the opponent's defensive tactics affect the form of attack patterns. For example, in the beige inbred CPB- WEzob strain, bites on the head are the dominant pattern, The hypothesis that these three factors allow for the whereas in random-bred albino Wistar CPB-WE rats, the observed variety in the form of ®ghts is supported by the dominant pattern is a bite directed at the back, a pattern fact that the intensity of the attack may be diminished by which is absent from the inbred strain [115]. The attacks decreasing stimulation intensity, treating the attacker with a derive from the same anatomical area in both strains [115, drug (e.g. l-propranolol; Kruk, unpublished results), or treating the opponent with a drug such as morphine. In all these cases the proportion of clinch ®ghts and jump-and-bite 1.4.2. Three factors determining the form of attacks decreases considerably. These ®ndings also clarify hypothalamically evoked aggression in the rat why it is questionable to classify brain-stimulation-elicited We argue that, upon stimulation of HAA in the rat, a aggression as offensive'' or defensive'' on the basis of multipurpose neural mechanism is activated that, under super®cial similarities with behavior expressed in natural natural conditions, subserves attack whenever it is required A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 Fig. 2. Changes in the attack pattern of six rats stimulated in the HAA, during attack threshold determinations lasting 15±20 trials, as a consequence of the i.p.
injection of 20 mg/kg morphine in 12 naive rats used as their opponents, compared with 12 control rats in a balanced design. Morphine injection 30 min before the start of a threshold determination completely immobilizes and anesthetizes the opponents, but does not change the latency to attack or the attack threshold in the untreated attacking rat (panels 1 and 2). However, morphinized opponents receive more hard-bites on their back (panel 3). Morphinized opponents exhibit fewer clinch ®ghts than placebo-treated controls (panel 4). Moreover, morphinized opponents are not subject to jump-and-kick attacks, in contrast to controls (not shown).
1.4.3. Behavioral concomitants of hypothalamic attack in One concomitant response is self-stimulation. However, the ability to elicit aggression cannot be predicted from the In contrast to earlier observations [217], it is now known rewarding or aversive properties of the stimulation. For that stimulation of different hypothalamic areas yields example, in one study, attacks were induced from 27 of different behaviors [120±122]. Within the region from 51 electrodes aimed at sites in the HAA. In six of these which attack can be elicited, other responses can be sites the rats learned self-stimulation; in 11 sites they obtained: piloerection, teeth chattering, quiet locomotion, learned to switch stimulation off; in eight sites the rats ¯ight, escape, and self-stimulation. Some of these concomi- learned both self-stimulation and the switch-off response, tant responses are more prepotent than others. For example, and in two sites they learned neither. From the 24 sites piloerection is an inconsistent concomitant response, which that did not produce attacks similar results were obtained often disappears after a few stimulations. Each of these [113]. A similar orthogonal relation between self-stimula- behaviors has its own typical distribution in the hypothala- tion and the elicitation of aggression was reported by Hern- mus, sometimes overlapping with aggressive responses, don et al. [95]. Because attack can be induced at sites that sometimes as an independent response. Brie¯y, the anato- produce self-stimulation, switch-off, and escape, as well as mical distribution of teeth chattering sites closely matches at sites that produce neither [113], it is likely that hypotha- that of attack sites, whereas ¯ight and locomotion sites may lamic attack in the rat does not derive from speci®c hedonic, be located rostrally and caudally far beyond the region aversive or ¯ight-inducing properties of stimulation.
where aggression can be elicited [120±123]. Teeth chatter- When observing hypothalamic attacks in rats, one is ing and piloerection are more prevalent in the area medial to tempted to use concomitant behaviors accompanying attack the fornix, whereas attack proper is more prevalent in the as criteria to classify the attacks into motivational categories subfornical area, giving way to social grooming in the direc- such as predatory'', fear-induced'', irritation- tion of the lateral hypothalamus. These ®ndings suggest that induced'', offensive'', defensive'' or territorial'' in cat and rat one ®nds a similar diminution of affectivity'' aggression [151]. However, since the neural substrates for when moving from medial to lateral through the hypotha- several different neural systems are near to, or overlapping, lamic area for aggression [121]. Piloerection is also a one another within the hypothalamus, stimulation may acti- component of the defensive attack pattern obtained from vate several systems and thus produce a mixed'' combina- the medial hypothalamus in the cat.
tion of responses. Therefore, in the rat it can be unclear A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 whether the responses elicited by stimulation arise from one attack in the rat is the expression of a general-purpose attack neural system or overlapping systems [172]. It is possible mechanism used in all kinds of settings, regardless of their that several of these concomitant responses form the overall motivational'' nature. In natural settings, attacks probably characteristic pattern of hypothalamically elicited attack are released when modulatory brain mechanisms (e.g.
behavior. Therefore, one cannot use concomitant responses medial amygdala, the prefrontal cortex, the septum or to classify hypothalamic attack into motivational categories.
PAG) are suppressed. Indeed, stimulation of HAA appar- However, such responses can serve as useful controls for ently overrides or bypasses those inhibitory mechanisms behavioral speci®city of drug effects [112, 118, 158, 219].
[112, 200, 201]. The mechanism that releases attack presumably is not con®ned to the hypothalamus, but 1.4.4. Hypothalamic attack and natural'' aggression includes such other regions as the PAG, medial amygdala, Rat aggression has been studied extensively in experi- lateral septum, and the ventral output pathways descending mental paradigms where brain stimulation was not caudally to the brain stem in the cat [201, 206] and rat [173, employed. The attacks which occur in naturalistic para- 175] in different degrees depending on the setting in which digms (such as in maternal aggression, offensive or defen- aggressive responses are functionally required.
sive territorial aggression, mouse-killing, and in the cornered rat'' paradigm) and in arti®cial paradigms (such as shock-induced ®ghting) all share similarities with 2. Central pathways mediating attack behavior hypothalamic attack. For example, the attack patterns and In attempting to understand the neural substrates of targets are similar. However, these attacks also differ from aggression, two concepts and some de®nitions should ®rst hypothalamic attack. Shock-induced ®ghting, for example, be noted. First, a crucial distinction must be made between is a purely defensive, re¯exive response to a painful stimu- two classes of neural structures. The ®rst class of structures lus [38±41]. It resembles the defensive response of an produces the expression of an attack response when stimu- attacked opponent in the upright position, but lacks the lated. These structures, and the pathways arising from them, purposeful, active approach and goal-directedness of mediate, or carry the neural signals necessary for, the motor hypothalamic attack. For a further comparison of hypotha- and autonomic aspects of aggression. Sites within these lamic aggression to aggression in other settings see Ref.
structures are termed, for example, defensive rage sites'' [112]. Such comparisons have led to the conclusion that or predatory attack sites''. The second class comprises hypothalamic attack in the rat is the consummatory limbic structures whose stimulation does not produce the response, or end-point behavior of the agonistic repertoire expression of an attack response; rather, stimulation of and, as such, constitutes a category in its own right. It these structures increases or decreases thresholds re¯ects the behavioral expression of a brain mechanism ( suppresses'' or facilitates'' the behavior respectively) that is activated when control over the behavior of another for responses elicited by concomitant stimulation of an organism is lost, and agonistic strategies such as threats, attack site. In other words, these structures modulate, or displays and warnings are insuf®cient to reinstate control.
mediate the modulatory effects on'' aggression, and are Under such conditions, inhibition over an attack±release termed modulatory sites''. For example, medial amyg- mechanism that can be activated from the hypothalamus is daloid facilitation of PAG-elicited defensive rage'' is short- overridden and a well-directed attack results. According to hand for a decrease in the threshold for defensive rage this concept, it is no surprise that the attack patterns behavior elicited by electrical stimulation of the PAG, observed during hypothalamic stimulation can also be which occurs as a result of electrical stimulation of the observed in territorial settings and resident±intruder para- medial amygdala''. Second, while in the cat, the pathways digms, in maternal aggression and in the cornered rat para- mediating predatory attack and defensive rage are clearly digm. Studies of feline hypothalamic attack addressing the separate, this particular separation has not yet been found in details of effector mechanisms, modulatory mechanisms, the rat, although ongoing research is beginning to map out and the speci®c sensory and endocrine changes involved, the efferent pathways from the hypothalamic area where support this view of the function of hypothalamic attack in grooming can be elicited (hypothalamic grooming area; natural settings [22, 73, 76, 206, 210, 211].
HGA) [176] and ¯ight-producing sites [173], as well as It is not likely that hypothalamic stimulation brings the rat HAA [173, 175]. The ®ndings of these studies generally into a motivational state of aggression'' in the classical parallel the ®ndings in the cat. The following discussion is sense of the word [116, 128]. The effects of hypothalamic based on work in the cat, referring to work in the rat when stimulation are quick to appear, and they disappear quickly after stimulation is terminated; also, lateral threat'' is absent from these attacks. Some of the attacked targets 2.1. Central pathways mediating attack behavior in the cat differ greatly from the targets attacked in natural agonistic settings. Stimulation seems to elicit unplanned ®ghting In the cat, the efferents from the hypothalamus and neigh- which is out of context from the functional point of view.
boring regions of the midbrain PAG which subserve aggres- These behavioral observations suggest that hypothalamic sion were initially examined by Chi and Flynn [56, 57] and A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 the ventral half of the PAG, and the ventral and lateral tegmental ®elds of the midbrain and pons (see Fig. 3).
The monosynaptic projection to the trigeminal motor nucleus may activate jaw-opening and -closing mechanisms for the biting component of the attack response. The projec- tion to the locus coeruleus may serve two functions. First, this nucleus projects to the intermediolateral column of the spinal cord [58, 153]; this projection would thus complete a disynaptic pathway for activation of the sympathetic nervous system, which is integral to the process of both predatory attack and defensive rage. Second, the locus coer- uleus contains the largest pool of noradrenergic ®bers that are distributed to the forebrain. Since the noradrenergic system facilitates defensive rage [26, 27], it is likely that these ascending ®bers provide a positive'' feedback mechanism to the hypothalamus and limbic system. This pathway could serve as a substrate for prolongation of the attack response. Interestingly, central noradrenergic facili- tation has also been proposed for aggression in the rat (reviewed in Ref. [91]). In a parallel fashion, a similar func- tion may be served by ascending ®bers associated with the perifornical hypothalamus that supply modulatory struc- tures such as the septal area, bed nucleus of the stria termi- nalis (BNST) and preoptic region [49, 186, 208]. The septal area is also involved in rat aggression [175].
Because the majority of efferents from predatory attack sites in the ventral PAG and pontine tegmentum project to the lateral hypothalamus [184], it is likely that these ®bers may complete an additional positive feedback loop.
Descending projections from PAG predatory attack sites pass for short distances to the lateral tegmental region from which attack can be elicited [34] and to the pontine Fig. 3. Diagram indicating the principal ascending and descending projec- tions of the perifornical lateral hypothalamus associated with quiet biting raphe complex, a region which, when stimulated, suppresses predatory attack behavior. Note the projections to the PAG, tegmental predatory attack [187]. The notion that the projection to the ®elds, locus coeruleus and motor nucleus of cranial nerve V. (From Ref.
raphe is associated with suppression of attack receives indir- [201] with permission.) ect support from the observation that parachlorophenylala- nine (PCPA), which blocks the rate-limiting enzyme in the later by others [75±77, 184]. The methods employed in biosynthesis of serotonin, facilitates the occurrence of this these studies included traditional tract-tracing methods response [133]. Thus, it would appear that the ventral PAG such as the Fink±Heimer method, tritiated amino acid auto- modulates the activity of the perifornical hypothalamus, radiography, and 14C-2-deoxyglucose autoradiography, as where the primary integration for this response takes place.
reviewed elsewhere [201, 206].
2.1.2. Pathways mediating defensive rage behavior 2.1.1. Pathways mediating predatory attack behavior The primary pathways associated with defensive rage Quiet biting attack sites are located along the rostro- arise from the medial hypothalamus [76, 77] and dorsal caudal extent of the lateral hypothalamus, but the most PAG [184]. Remarkably, ®bers arising from defensive sensitive region is the perifornical region [201, 206]. In rage sites in or near the ventromedial hypothalamus pri- the brainstem, attack sites are located in the ventral aspect marily pass rostrally, terminating principally upon neurons of the PAG [184], ventral tegmentum [25] and as far caud- within the medial anterior hypothalamus±preoptic zone, an ally as the lateral tegmental ®elds of the pons [34]. The most area from which this response could also be elicited. Inputs important cells which give rise to ascending and descending to this zone include axons from limbic regions such as the ®ber systems mediating the expression of predatory attack amygdala, septal area and BNST [48, 49, 211]. The are situated in the perifornical lateral hypothalamus.
descending ®bers which innervate the PAG mostly originate Descending ®bers from the lateral hypothalamus project to from this zone (see Fig. 4). This pathway from medial nuclei that appear to be essential for predatory attack, hypothalamus to dorsal PAG constitutes the principal path- including the trigeminal motor nucleus, the locus coeruleus, way for defensive rage in the cat. These ®ndings provided A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 Fig. 4. Diagram indicating the principal ascending and descending projections of the medial hypothalamus associated with defensive rage behavior. Note that ®bers mainly ascend from the ventromedial hypothalamus to the anteromedial hypothalamus and preoptic region and that ®bers that supply the PAG arise principally from the anteromedial hypothalamus. (From Ref. [206] with permission.) the basis for further studies, described below, concerning behavior [201, 202, 205]. Because little is known about the role of catecholamines and excitatory amino acids in the transmitters involved, we will only brie¯y discuss this pathway.
pathways from the amygdala.
In contrast to the predatory attack system, the majority of Several important modulatory pathways issue from the ®bers arising from PAG defensive rage sites pass caudally, amygdala. The most well-documented pathway, the stria to the locus coeruleus, sensory and motor nuclei of the terminalis, arises from the medial nucleus, medial aspects trigeminal complex, and neighboring regions of the of the basal complex, and the area in and around the cortical midbrain and pontine tegmentum. The projections to the nucleus. These ®bers arise from modulatory regions which, locus coeruleus may serve the same two functions as when stimulated, facilitate defensive rage and suppress noted above for the predatory attack system. Other path- predatory attack [42, 48, 70, 211]. The primary target of ways governing autonomic regulation may include ®bers these ®bers is the medial hypothalamus, in which they from the caudal PAG which appear to descend to autonomic terminate over a wide area, extending from the anterior- nuclei of the lower brainstem [24]. The efferents to the preoptic zone to the posterior aspect of the ventromedial trigeminal complex may mediate the vocalization that nucleus [110, 211, 228]. In contrast, ®bers which arise normally accompanies defensive rage. Similar to the preda- from the central nucleus, lateral aspects of the basal tory attack system, some of the ®bers arising from the dorsal complex, and the lateral nucleus are distributed to the PAG project rostrally to portions of the medial hypothala- BNST and, via the ventral amygdalofugal pathway, through mus that produce defensive rage, and may complete a simi- the medial forebrain bundle to the lateral hypothalamus, lar positive feedback loop, allowing for the response to be PAG, and autonomic nuclei of the caudal medulla. It has prolonged. However, it should be noted that the PAG been shown that the cells of origin of these ®bers are asso- contains sites which, when stimulated, can facilitate or ciated with suppression of defensive rage and facilitation of suppress defensive rage or predatory attack elicited by predatory attack [42, 48, 70]. Thus, strikingly, some cell hypothalamic stimulation [165, 229]. The pathways from groups in the amygdala facilitate predatory attack but the PAG for predatory attack and defensive rage are suppress defensive rage and other cell groups do the oppo- summarized in Fig. 5.
site. It is likely that the outputs of the amygdala to the medial hypothalamus and PAG constitute direct routes by 2.1.3. Limbic pathways that modulate predatory attack and which the amygdala modulates aggressive reactions, and the output to the BNST is an indirect route. Evidence in support Limbic structures give rise to pathways that synapse upon of this indirect route is that: (1) the BNST projects directly hypothalamic or PAG cells and modulate aggressive to the medial hypothalamus and PAG [97, 228]; (2) BNST A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 Fig. 5. Diagrams indicating the principal efferent projections from PAG sites associated with defensive rage (left side) and predatory attack (right side). Note that ®bers associated with defensive rage arising from the PAG are distributed rostrally to the medial preopticohypothalamus from where this response can also be elicited and caudally to the locus coeruleus, tegmental ®elds and trigeminal complex. Also note that the distribution from predatory attack sites is more limited in which a primary projection ascends and synapses in the posterior lateral hypothalamus where this response can also be elicited. Descending projections supply the central tegmental ®elds and median raphe. (From Ref. [206] with permission.) stimulation results in modulation of both defensive rage and with the systematic distribution studies by Kruk and cowor- predatory attack [186]; (3) infusion of an opioid agonist into kers [114, 119, 120], taking into consideration the dimen- the BNST results in suppression of defensive rage [51]. The sions of electrodes and stimulation techniques used, it seems nucleus accumbens modulates defensive rage elicited from clear that all these responses have been induced in a subfor- the medial hypothalamus [52].
nical area (Fig. 6). It is likely that all these responses were obtained from the same neural system within that area.
2.2. Neural substrates of aggressive behavior in the rat HAA extends laterally from the arcuate nucleus and medial aspect of the ventromedial nucleus to the ventral 2.2.1. Relationship of anatomical loci to hypothalamic aspect of the lateral hypothalamus. It extends rostrally attack responses and structure of the hypothalamic attack from the lateral edge of the ventromedial nucleus towards the frontal pole of the ventromedial nucleus and anterior The ®rst studies in rat, conducted with limited numbers of hypothalamic nucleus [113, 114, 119, 120]. HAA is implanted electrodes, suggested that different types of approximately the same in male and female rats [114, aggression could be induced from different hypothalamic 119] as well as in different strains of rats [115, 120]. Lesions areas. In contrast to these reports [12, 105, 108, 161±163, of HAA reduce aggression evoked by an intruder in a terri- 223, 231], it was later found that the whole region of the torial setting [8, 154, 159]. Marginal sites within HAA yield HAA basically yields the same set of aggressive responses, less intense responses. These studies suggest that a speci®c and that the variations in response can be accounted for by hypothalamic mechanism is involved in the control of the intensity of stimulation, posture of the opponent, and the aggression, although the sites producing aggression are simultaneous activation of concomitant responses [114, not limited to a single nuclear group. See Figs. 6 and 7.
116, 118, 120±123]. If one compares the regions of the Following a novel classi®cation of hypothalamic areas hypothalamus where other investigators [12, 105, 108, based on cytoarchitectonic criteria [81, 82], it is now 161±163, 173, 223, 231] elicited aggressive responses recognized that HAA almost completely coincides with A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 Fig. 6. Attack-inducing sites in the hypothalamus of the rat plotted in the atlas of Geeraedts et al. [81, 82]. Adapted from Ref. [175]. The attack area largely coincides with the intermediate hypothalamic area, and the ventro-lateral pole of the ventromedial nucleus of the hypothalamus. Abbreviations: AHA, anterior hypothalamic area; ci, capsula interna; DHA, dorsal hypothalamic area; DMH, dorsomedial hypothalamic nucleus; fx, fornix; LHN, lateral hypothalamic nucleus; LPOA, lateral preoptic area; mt, mammillothalamic tract; ot, optic tract; PFX, perifornical nucleus; PVH, paraventricular hypothalamic nucleus; sm, stria medullaris; VMH, ventromedial hypothalamic nucleus; ZI, zona incerta.
the intermediate hypothalamic area (IHA). IHA is about setting [148]. This differs from the cat, in which such lesions 0.5 mm3 in size, and contains about 17 £ 103 neurons and block aggression elicited by stimulation of the stria termi- about 150 £ 106 synaptic contacts. About half of these nalis [72]. In the rat, though HAA efferents clearly differ contacts are symmetrical contacts, the other half being from the efferents of the HGA, which is located in the para- asymmetrical. The synapse-to-neuron ratio is about 9 £ ventricular nucleus and adjacent dorsomedial hypothala- 103, whereas there are only 170 axo-somatic contacts per mus, they may not be speci®c for attack behavior, since soma. IHA may be homologous to the anterior hypothala- lesions of the PAG do not signi®cantly affect hypothalamic mus in the cat. The projection from the lateral septal area to attack or hypothalamic self-grooming [148, 220]. The the HAA consists of small unmyelinated varicose ®bers effects of hypothalamic stimulation are possibly mediated forming axo-dendritic asymmetrical contacts in the IHA by the ventro-caudal projections of HAA (see also [9]).
[1]. We assume that hypothalamic aggressive responses Stimulation of HAA activates ascending projections are elicited by the overriding of local tonic inhibition, terminating in and projecting through the medial preoptic since local infusion of the GABAA antagonist bicuculline area [173, 175] where, occasionally, attack has been induces similar attacks [174]. Similar results were reported induced in the proximity of the ventral supraoptic commis- for the GABA antagonist picrotoxin [9], and for the combi- sure. This commissure, which may connect to neurons in the nation of a glutamate agonist and bicuculline [91].
IHA/HAA or the adjacent anterior hypothalamus, has been suggested as a key element in the attack-relevant mechan- 2.2.2. Efferent pathways involved in hypothalamic attack in isms in the hypothalamus [173]. Moreover, Adams [9] has shown that the GABA antagonist picrotoxin elicits aggres- In the rat, as in the cat, the hypothalamic attack area sive behavior when injected into the area where electrical projects extensively to the PAG. In rat, in the regions of stimulation elicits attack, but also in the adjacent frontal the PAG which receive projections from HAA, attack simi- area, ventrally in the anterior hypothalamus.
lar to hypothalamic attack can be elicited, although not as In the cat, clear-cut anatomical boundaries are present for easily as from HAA [147], and the responses are sometimes different aggressive responses. In the rat, the apparent accompanied by severe motor disturbances. However, absence of such boundaries has complicated the task of selective destruction of the entire PAG only slightly and tracing the connections of the system to more caudal regions transiently reduces attack elicited by hypothalamic stimula- of the brainstem, where a similar form of attack can be tion and aggression provoked by an intruder in a territorial induced by electrical stimulation [147, 226]. However, the A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 projections of the IHA have now been studied in detail using that the majority of the projections from these two areas the Phaseolus vulgaris leucoagglutinin (PHA-L; see Fig. 7) have nothing to do with the speci®c behavioral conse- [175]. It now seems likely that HAA projects to many areas quences of stimulation, or that the behavioral speci®city is that affect aggression [226]: its projections pass through due to subtle differences in projections within the target several of the structures relevant for aggression in the cat, structures. There are indications for the latter explanation.
such as the ventral tegmental area (VTA), raphe magnus, Fig. 7 illustrates how HGA and HAA efferents have differ- PAG, locus coeruleus, the A5 region of the brainstem ent preferences for speci®c structures. As expected, HGA, tegmentum, and the nucleus tractus solitarius, and are but not HAA, projects clearly to the arcuate nucleus and covered with varicosities or boutons-en-passant, which median eminence. Moreover, HGA projects much more may release neurotransmitter into these structures. These extensively to the ventral tegmental area, raphe magnus, projections presumably subserve similar functions as locus coeruleus and dorsal motor nucleus of the vagus and suggested for the cat (i.e. autonomic or endocrine integra- nucleus tractus solitarius. HGA projects to ventrolateral tion, or feedback loops). For a discussion of the involvement PAG, whereas HAA projects to dorsal and dorsolateral of endocrine mechanisms and hypothalamic behavioral PAG. Since aggressive behavior is associated with high regulation see Ref. [66].
arousal, and grooming is associated with the absence of arousal, it is interesting to note that the parts of the PAG 2.2.3. Speci®city of the projections from HAA/IHA efferent to HAA are associated with blood pressure PHA-L tracing studies by Roeling and coworkers [175, increases whereas parts efferent to HGA are associated 176] make it possible to get an impression of the behavioral with decreases. HAA projects preferentially to the adjacent speci®city of HAA and HGA efferents. These studies ventromedial nucleus of the hypothalamus and to the para- revealed eight different streams of thin unmyelinated vari- taenial and mediodorsal thalamic nuclei; HGA projects cose efferents from each of these areas. The streams from preferentially to the medial preoptic area and anteroventral HAA split and end in at least 26 different areas, projecting parts of the periventricular nucleus. The most pronounced frontally as far as the nucleus accumbens and the lateral differences between HGA and HAA are found in the septum, dorsally as far as the lateral habenular nucleus projections to the lateral septal nucleus: HGA projects and caudally as far as the nucleus of the solitary tract and almost exclusively to the ventral part of this nucleus, ventrolateral medulla. The projections from HGA are simi- whereas the HAA projects almost exclusively to the dorso- lar. Fibers also emerge from HGA in eight unmyelinated lateral portion of the intermediate part [175, 176]. The septal streams, covered with varicosities, follow paths very similar projections of the HAA are of interest because the lateral to those from HAA, and terminate in at least 23 areas. At septum sends projections to the HAA, suggesting that the least 14 brain areas receive similar projections from both rage that is a well-known consequence of the interruption of HGA and HAA (Table 1). These similarities suggest either septal±hypothalamic connections [10, 11, 13±16] may be Fig. 7. Schematic representation of the speci®c projections of the hypothalamic attack area (HAA), as contrasted with the projections speci®c to the hypothalamic grooming area (HGA). For details on the 16 areas to which both HAA and HGA project (not shown here) see Refs. [175, 176]. Abbreviations: Arc, arcuate nucleus; CGD, dorsal part of the PAG; CGld, dorsal portion of the lateral part of the PAG; CGlv, ventral portion of the lateral part of the PAG; DMV, dorsal motor nucleus of the vagal nerve; LC, locus coeruleus; LSIdl, dorsolateral portion of the intermediate part of the lateral septal nucleus; LSV, ventral part of the lateral septal nucleus; MD, mediodorsal thalamic nucleus; ME, median eminence; MnPO, median preoptic nucleus; NTS, nucleus of the solitary tract; PeAV, anteroventral part of the periventricular nucleus; Pt, parataenial thalamic nucleus; RMg, raphe magnus; VMH, ventromedial hypothalamic nucleus; VTA, ventral tegmental area.
A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 according to this model, four visual areas (the lateral super- Brain areas receiving projections from both the hypothalamic grooming ior colliculus, the lateral pretectal area, and the dorsal and area (HGA) and the hypothalamic aggression area (HAA), according to ventral lateral geniculate nuclei) are preferentially activated PHA-L injections (adapted from Refs. [175, 176]). Only areas that received projections in all rats injected at attack sites and all rats injected at groom- during HAA stimulation, but the PAG is not.
ing sites are listed Some support for this model is given by the facts that: (1) hypothalamic aggression has, on occasion, been elicited by stimulation of the region anterior and ventral to the HAA, Anterior commissure proximal to the optic tract; (2) the HAA extends from the Bed nucleus stria terminalis Central tegmental ®eld IHA into the ventrolateral part of the VMH [119, 123].
However, only the VMH, zona incerta and cuneiform area Lateral hypothalamic area have been shown to be connected directly to the HAA, and Lateral habenular nucleus only the ventrolateral part of VMH is considered as part of Lateral preoptic area the aggression-relevant network in the study by Roeling and Lateral septal nucleus, intermediate part Lateral septal nucleus, ventral part coworkers. Roberts' study suggests that the peripeduncular Mesencephalic PAG nucleus is most speci®cally associated with the HAA, and Medial amygdaloid nucleus the septal area has no place in Roberts' proposed model Medial preoptic area [173]. Roeling and coworkers suggest that the most speci®c Paraventricular thalamic nucleus output pathway for the HAA is a speci®c part of the lateral Substantia innominata, pars subcommisuralis Substantia innominata, pars sublenticularis septum, and the peripeduncular nucleus is absent from the projections studied by them. It should be noted that, in the cat, a pathway from the lateral hypothalamic-predatory due to interruption of a feedback loop [10, 11, 13, 14, 16, attack region to the lateral septal area has been identi®ed 43]. Moreover, HAA projections form peculiar pericellular [75]; these authors interpreted this pathway as a feedback baskets around septal cells that could interact with the sero- tonergic baskets around septal cells [80]. Thus one can spec- Four methodological reasons could explain the con¯ict- ulate that the effects of serotonin agonists on hypothalamic ing conclusions derived from these rat studies. First, the attack [112, 113] and on aggression induced by other means brain activity in anesthetized animals which are continu- [155, 157, 158] are due to interference with a HAA±septal ously stimulated for long durations, at suprathreshold inten- feedback loop.
sities, may differ from the activity induced during the The fact that HAA projects to an area does not prove that milder, short stimulations used to elicit attacks in awake such a projection mediates hypothalamic attack. Clues animals. Second, even though the electrodes are in the about the involvement of speci®c areas could be derived same area as in other studies (i.e. in the IHA), larger areas from the study of the patterns of activation caused by stimu- may have been activated. Third, stimulation may also have lation of IHA/HAA. However, an extensive study by had antidromic effects; therefore, deoxyglucose methods Roberts and Nagel, utilizing deoxyglucose uptake as a meta- may reveal projections to and from the HAA, whereas bolic marker during stimulation of sites in HAA [173], is PHA-L reveals only the latter. Fourth, the emphasis on the hard to reconcile with the PHA-L projection studies. In this predominance of contralateral effects in the deoxyglucose study, hypothalamic sites that produced upward ¯ight beha- study may be due to the statistical method used to demon- vior were used as controls for speci®city of effects. Deoxy- strate behavioral speci®city by contrasting hypothalamic glucose uptake in 62 sites was quanti®ed. Deoxyglucose ¯ight against hypothalamic attack. However, the raw data labeling was more intense on the side of the brain ipsilateral in that study clearly show that the ipsilateral effects are at to stimulation in both attacking rats and controls. Thirty-two least as prominent as the contralateral effects. The conclu- brain areas were signi®cantly more activated in attacking sion can only be that many pathways may be responsible for rats than in controls. Curiously, there were more differences stimulation-induced aggression, and that additional studies from the controls at contralateral sites (28 differences) than and novel methods (e.g. c-Fos) are required to unravel the ipsilateral sites (21 differences). In contrast, in the PHA-L studies, contralateral projections from the HAA/IHA were not much in evidence [175]. Based upon the deoxyglucose 2.2.4. Functional relationships of other limbic structures to data and data from the general anatomical literature, but not hypothalamic attack in the rat from the PHA-L studies, a model was proposed by Roberts.
The HAA overlaps with the projection areas of the medial According to this model, the efferents for aggression run amygdala to the medial hypothalamus [113, 114, 119, 120, from the HAA, via the ventromedial nucleus of the hypotha- 130]. Infusion of arginine-vasopressin (AVP) into the lamus (VMH), to the ipsilateral and contralateral ventral medial amygdala increases territorial aggression and supraoptic commissure to continue to the ventral zona partially counteracts the gradual decrease in territorial ®ght- incerta, the subparafascicular nucleus, the peripeduncular ing caused by castration [109]. It is known that the expres- nucleus and the cuneiform area in the brain stem. Also sion of endogenous central vasopressin is dependent on A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 testosterone. Therefore, it is notable that castration causes region. Third, with the microinjection technique, drug increases in hypothalamic attack thresholds that can be concentrations may exceed concentrations of the amine or reversed by testosterone [33]. Ovariectomy does not affect peptide that normally acts at these receptor populations; for thresholds [114]. Infusion of the serotonergic drug, quipa- this reason, it is possible that systemic and intracerebral zine, into the medial amygdala reduces natural mouse kill- microinjections of a compound may yield different results.
ing [166]. In addition, the medial amygdala in the rat and cat Fourth, if the volume of injection is too large, the drug may seems to have a role in the learning of social signals and the diffuse through the brain to affect areas other than the target signi®cance of defeat [3, 109, 130, 224]. As noted above, area, as may have been the case for Ref. [99].
connections of the amygdala with the hypothalamus may In the rat, much work has examined the involvement of control hypothalamic attack release mechanisms with neurotransmitters in aggression. However, since most of respect to these aspects of aggression.
these studies have not used brain stimulation to elicit Stimulation of the deeper orbital layers of the prefrontal aggression, they fall outside the scope of this review. See cortex inhibits attacks elicited from the hypothalamus in rats the review by Miczek et al. [142] for an account of this [65]. This parallels the ®ndings in the cat, where stimulation of the lateral or medial prefrontal cortex blocked predatory attack elicited from the lateral hypothalamus [203, 204].
3.1. Evidence for the presence of a cholinergic mechanism The pathway mediating this effect may be a multisynaptic projection from the prefrontal cortex to the lateral hypotha- lamus, via the mediodorsal and midline nuclei of the thala- 3.1.1. Systemic injections Several early studies demonstrated that systemic injec- tions of muscarinic agonists could facilitate defensive rage in the cat [83, 124, 234]. Berntson and Leibowitz [37] 3. The neuropharmacology of brain-stimulation-induced extended these ®ndings by showing that injections of the aggressive behavior muscarinic agonist, arecoline, could induce biting attack, which, in turn, was blocked by pretreatment with the Studies of neurotransmitter involvement in stimulation- muscarinic antagonists atropine or scopolamine. A later induced aggression have employed two approaches. In the study [35] showed that pretreatment with nicotine can ®rst approach, an agonist and/or antagonist for the putative suppress naturally evoked or arecoline-induced predatory transmitter is injected systemically and the effect of the attack and defensive rage. Similar results were also injection upon the threshold or latency is measured over observed by Katz and Thomas [100] who noted that the time. This approach can provide an overall assessment of threshold for hypothalamically elicited predatory attack whether the transmitter is involved in aggression. In addi- was elevated following scopolamine administration.
tion, it has the advantage of constituting the clinical route of However, Baxter [30] noted that atropine or scopolamine administration of drugs such as carbamazepine. The de®- had little effect upon hypothalamically elicited defensive ciency of the approach is that it does not reveal the locus of rage, other than to produce ataxia. Interestingly, scopola- action of the drug. In addition, with the use of this approach, mine does not affect thresholds for hypothalamic attack in one must determine whether the effects of drug administra- rats; perhaps the stimulation overrides or bypasses local tion are speci®c to the process under investigation. In the cholinergic blockade [112, 118].
second approach, the agonist or antagonist is microinjected into a speci®c region within the brain, usually at an attack 3.1.2. Intracerebral injections site, and the effects of drug infusion are identi®ed. It should Further support for the notion that muscarinic receptors be noted that the use of cannula-electrodes allows investi- are involved in the expression of aggression was gained gators to electrically stimulate an area and to infuse a drug from several studies. Beleslin and Samardzic [31] observed or retrograde tracer into the same area. This approach can hissing and growling following intraventricular injections of provide clues about the presence or absence of a putative muscarine chloride, which could be blocked by atropine or transmitter at a given synaptic region and its possible role in scopolamine. Such effects have also been reported when aggression, with four caveats. First, it is entirely possible carbachol was placed into the medial hypothalamus [45, that a receptor is present at a synapse, while the neurotrans- 46, 99, 177, 178, 221] or PAG [29, 94]. In an extensive mitter usually associated with that receptor is not present. In mapping study, Allikmets [17] injected acetylcholine into such a case, the drug would act upon receptors at the defensive rage sites and observed similar behavioral effects; synapse, resulting in a change of behavior, and this would these sites were primarily localized to the periventricular lead one to the false conclusion that the transmitter at that hypothalamus and PAG. Defensive rage can also be synapse has been identi®ed. Second, this approach can lead observed following cholinergic stimulation of the septal to a ®shing expedition'' in which many different drugs are area [94] or dorsomedial amygdala [18], areas usually tested without a suitable rationale, unless there is a sound considered to be modulatory. However, these areas have rationale that the transmitter is present at the synaptic low thresholds for epileptiform activity, and stimulation of A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 them produces attack behavior only at current levels which is the only drug that facilitates hypothalamically elicited produce seizures [200, 201]. Thus, the responses observed attack [118].
by these authors may have been secondary to seizure activ- Other indirect evidence in support of a serotonin mechan- ity induced by chemical stimulation. Somewhat surprising ism is that acute treatment with the tricyclic antidepressants results were obtained by Kono and coworkers [106, 107] chlorimipramine and imiprimine (which may be more effec- who administered intrahypothalamic injections of acetyl- tive against catecholamines) suppresses predatory attack in choline or carbachol. They noted that low doses of these the cat [68, 69]. These drugs are believed to inhibit prefer- drugs did not alter spontaneous behaviors, but suppressed entially the uptake of amines in serotonergic neurons when electrically elicited defensive rage. In contrast, higher doses administered acutely [53]. In addition, if the animal is elicited defensive rage. Further, choline or physostigmine pretreated with PCPA, chlorimipramine does not suppress elevated attack thresholds, whereas nicotine was ineffective; attack, suggesting that endogenous levels of serotonin are these inhibitory effects were antagonized by atropine but not required for the antidepressant's inhibitory effects. Further- curare, further supporting the notion that muscarinic more, when the animals were treated with the serotonin mechanisms are involved. They also observed that the precursor 5-hydroxytryptophan (5-HT), the suppressive effects of microinjections of acetylcholine into the medial effects of chlorimipramine were restored. It is of interest hypothalamus were blocked when lesions were placed into to note that acute imipramine administration does not the stria terminalis, which led them to conclude that this suppress defensive rage [68] and, in fact, even facilitates pathway is cholinergic [107].
this response [137, 164]; this may be due to an elevation Regarding predatory attack, one study reported that of norepinephrine levels (see discussion below). Chronic carbachol microinjections into the ventral tegmentum of administration of tricyclics might have different effects on cats produced defensive rage followed by directed killing feline aggression. It is possible that since tricyclics, like the of a mouse [99]. The fact that both types of aggression selective serotonin reuptake inhibitor paroxetine, elevate followed the injections suggests that they activated a wide levels of 5-HT in the synaptic cleft when administered area containing separate regions for each form of attack.
acutely, they, like paroxetine, also lead to a down-regulation These studies indicate that cholinergic drugs act through of 5-HT2 receptors when given chronically. Since acute muscarinic receptors in the medial hypothalamus and PAG treatment of rats with antidepressants results in a decrease to modulate defensive rage and (possibly) predatory attack.
in aggression, whereas chronic treatment results in an However, a more convincing experiment to show that acet- increase, an effect possibly due to down-regulation of 5- ylcholine is involved in aggression would require that HT2 receptors [146], perhaps chronic treatment of cats microinjection of a cholinergic antagonist into a synaptic with tricyclic antidepressants would enhance predatory region critical for the expression of attack inhibits that attack and/or defensive rage.
response when elicited either under natural conditions or by stimulation of another attack site.
3.2.2. Intracerebral injections 3.2. Evidence for serotonergic involvement in attack In two separate studies, Golebiewski and Romaniuk [86] behavior in the cat and Romaniuk et al. [179] demonstrated that serotonin, injected into hypothalamic sites from which carbachol can 3.2.1. Systemic injections elicit affective defense, inhibits the attack response. Conver- A serotonergic mechanism may be involved in aggres- sely, when methysergide, a serotonin antagonist, is injected sion, as suggested by the consistent effects of systemically into such sites, the attack response is enhanced. Moreover, injected PCPA. For example, in one study PCPA induced when 5,6-dihydroxytryptamine (5,6-DHT), which selec- both hypersexuality and predation [71]. Furthermore, tively destroys serotonin neurons, is microinjected into the several studies showed that PCPA facilitates (i.e. shortens dorsal raphe, there is a decrease in brain serotonin coupled the latency and lowers the threshold for) hypothalamically with an enhancement in carbachol-induced defensive rage.
elicited predatory attack [100, 133]. One site where seroto- Thus, it is reasonable to conclude that serotonin normally nin probably acts to modulate this response is the trigeminal serves to suppress defensive rage by acting, at least in part, motor nucleus, which is needed for biting to occur. Support upon neurons in the medial hypothalamus.
for this view was provided by MacDonnell and Fessock The raphe system projects to the forebrain, brainstem [132] who demonstrated that evoked potentials in the tegmentum, limbic system and even the trigeminal motor trigeminal motor nucleus elicited by stimulation of parts nucleus. A recent set of experiments tested the effects of of the basal ganglia from which jaw-opening could also microinjections of selective 5-HT compounds into the PAG be elicited were enhanced by PCPA treatment. These effects upon defensive rage elicited from the medial hypothalamus may not be limited to the cat: PCPA reduces natural preda- [188]. Defensive rage was suppressed following microinjec- tion time of the grasshopper mouse upon crickets [141].
tions of the 5-HT1A receptor agonist, 8-OHDPAT; pretreat- Regarding defensive rage behavior, systemic administration ment of the PAG with microinjections of the 5-HT1A of PCPA facilitates this response [133]; and in the rat, PCPA antagonist p-MPPI blocked this effect. Facilitation of A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 defensive rage followed microinjections of the 5-HT2/1C of hypothalamic attack in the rat by a limited class of sero- agonist, (1) DOI hydrochloride [188].
tonergic drugs, acting perhaps through 5-HT1B receptors, However, these studies did not fully identify (1) the sites seems to parallel the overall suppressive effects of this where serotonin affects neurons associated with attack, (2) neurotransmitter upon aggressive reactions reported above the actions of the respective 5-HT subtypes upon aggres- sion, or (3) the cellular mechanisms of action of each of the The behavioral selectivity of the effects of serotonergic drugs was demonstrated by the fact that other behavioral consequences obtained from the same electrodes in the same animals were hardly affected by these drugs. Con- 3.2.3. Effects of serotonergic agents upon hypothalamic versely, stimulation-induced locomotion was facilitated by attack in the rat scopolamine and amphetamine at doses that did not affect In an initial set of experiments, PCPA was shown to hypothalamic attack elicited from the same sites. The phar- decrease 5-HT levels and facilitate hypothalamic attack macologic pro®le of stimulation-induced teeth chattering [118]. Similarly, infusion of 5,7-DHT, into the hypothala- and escape resembles the pro®le of attack.
mus resulted in similar facilitation of offensive'' aggres- sion in territorial ®ghting [222]. For a review of the involvement of serotonin and other transmitters in aggres- sive behavior, see Ref. [143].
In a series of studies, the effects of serenic'' compounds (which have high af®nities for 5-HT recep- The overall results obtained in cat and rat indicate that tors [158]) upon hypothalamic attack thresholds were serotonin mechanisms suppress aggression. Moreover, for determined using an up-and-down procedure (variation the rat, the combined results of studies involving lesions, of the Method of Limits) [112, 114, 117, 118, 219, infusions of selective neurotoxins into the hypothalamus [8, 230]. Drugs and doses were chosen which severely affect 154, 160, 222], or application of selective anti-aggressive territorial or maternal aggression. Whenever possible, drugs acting through 5-HT receptors, strongly suggest that concomitant responses such as teeth chattering, locomo- the hypothalamic attack release mechanism is involved in tion and escape elicited from the same electrodes were aggression in natural settings.
used as controls for behavioral speci®city. Details on The following line of evidence supports this conclusion.
procedures can be found in Refs. [118, 219]. Table 2 Fluprazine and TFMPP are prototypes of the so-called summarizes the effects of drugs on thresholds, obtained serenics'' which have high af®nities for 5-HT1 receptors by different groups in different strains of rats. The effects [158], and have been shown to inhibit hypothalamic attack are expressed as percentage increase with respect to vehi- selectively in both sexes and in different strains (CPB- cle control. All drugs were tested in adult males, except WEzob rats, albino random bred CPB-WI Wistar rats and alcohol which was tested in adult females. All drugs Tryon Maze Dull rats) [112, 114, 118, 157, 158, 219].
have been shown to inhibit aggression in natural settings Serenics also reduce natural'' aggression provoked by such as territorial or maternal aggression, and usually at the presence of an intruder endangering offspring or terri- lower doses than used here. Only a few drugs strongly tory [155±158, 160]. Behavioral sequence analysis of the increased thresholds. The phenyl-piperazines quipazine, effects of an early prototype of the serenics [155] in a terri- serenic'' compounds ¯uprazine and its metabolite torial setting reveals that serenics do indeed inhibit the most TFMPP, but also dl-propranolol, selectively elevated violent parts of the agonistic pattern such as ®ghting and thresholds and also displayed steep parallel dose±effect biting. The rest of the agonistic pattern remains relatively curves, suggesting a common mechanism of action.
unaffected by these drugs. Thus, drugs that inhibit hypotha- Fluvoxamine and oxazepam weakly affected thresholds.
lamic attack also inhibit attack in natural settings. In In contrast, dl-amphetamine, scopolamine, 8-OH-DPAT contrast, many drugs that do not inhibit hypothalamic attack (a selective 5-HT1A agonist), mianserine (a 5-HT2 antago- do inhibit aggressive behavior in a territorial setting [160].
nist) and chlordiazepoxide had no effect.
However, drugs such as scopolamine and amphetamine The inhibitory effects of propranonol could be due to its seem to achieve such effects by reducing aggressive af®nity for central 5-HT receptors [88, 144, 145] or to adre- postures due to the induction of stereotypy and locomotion nergic blocking properties. The drug has a stereospeci®c effect on territorial aggression [233] and hypothalamic It has been suggested that the anti-aggressive properties attack (Kruk, unpublished results). Fluprazine and propra- of the serenics are due to anxiety-promoting properties [101, nolol facilitate social cooperation between rats in the same 102]. Since the potent anxiolytic oxazepam slightly inhibits way [32]. Interestingly, propranolol and TFMPP have simi- hypothalamic attack, such a conclusion may not be justi®ed.
lar discriminative stimulus properties [85].
Anxiogenics, such as inverse benzodiazepine agonists, have Strikingly, many drugs that affect aggression in natural just begun to be studied [see section 3.9 for further settings do not affect hypothalamic attack. Thus, modulation A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 Pharmacological pro®le of hypothalamic attack for systemically administered drugs in rats. Drugs that suppress hypothalamic attack increase the threshold current required to induce attack. The increases are expressed as a percentage of the vehicle condition. Only the effects at the maximum dose are given.
Adapted from Refs. [112, 118, 158, 219]. Notice that PCPA (parachlorophenylalanine) facilitates hypothalamic attack, and hypothalamic attacks are relatively insensitive to many drugs that do affect other forms of aggressive behavior, and that, apart from the dopaminergic antagonist haloperidol, drugs displaying serotonergic agonism are among the most effective drugs Increase from control (%) Dose range (mg/kg) 0.5±2.0 i.p.
0.25±1.0 i.p.
50 (at highest dose only) 250±2000 p.o.
0.5±2.0 p.o.
1.25±10 i.p.
100 single dose p.o.
50 single dose i.p.
0.05±0.2 s.c.
0.125±1.0 p.o.
1.25±10 i.p.
375 single dose i.p.
3.3. Dopaminergic involvement in stimulation-induced D1 antagonist, SCH 23390. Thus, it was concluded that attack behavior in the cat dopaminergic facilitation of defensive rage is mediated primarily by D2 receptors [212].
3.3.1. Systemic effects Predatory attack is also facilitated via D2 receptors [190].
Dopaminergic mechanisms are thought to facilitate Apomorphine administration facilitated the occurrence of defensive rage and predatory attack. One indirect piece of this response; and spiperone, but not SCH 23390 (a D1 evidence is that electrical stimulation of the ventral tegmen- antagonist), elevated response thresholds when adminis- tum or substantia nigra, the primary sources of dopaminer- tered alone, and blocked the facilitatory effects of apomor- gic innervation of the forebrain, facilitated defensive rage phine when delivered before apomorphine. In conclusion, it [63, 185]. Direct evidence was obtained by Maeda et al.
would appear that dopaminergic mechanisms facilitate [136] and Maeda and Maki [135] who showed that thresh- defensive rage and predatory attack, whereas serotonin inhi- olds for hypothalamically elicited defensive rage decreased bits these responses.
following systemic administration of the indirect and direct dopamine agonists methamphetamine and apomorphine 3.3.2. Intracerebral injections respectively. Maeda and coworkers also showed that halo- Dopaminergic ®bers from the ventral tegmentum and peridol, a non-selective dopamine antagonist, elevated the adjoining regions of the far medial hypothalamus project defensive rage threshold.
rostrally to the limbic forebrain and supply, among other Another study replicated and extended these ®ndings.
regions, the medial anterior hypothalamus±preoptic zone, a First, it was found that haloperidol injected alone elevated region critical for the expression of defensive rage in both thresholds, or, when injected before apomorphine, blocked cat and rat. Accordingly, the model shown in Fig. 8 its facilitatory effects. Then, these authors found that the proposes that catecholaminergic ®bers facilitate defensive relatively selective D2 agonist, LY 171555 (Quinpirol), rage, particularly at the level of the anterior medial hypotha- but not the selective D1 agonist, SKF 38393, facilitated lamus (although interactions at other levels along the defensive rage. Moreover, the facilitatory effects of apomor- limbic-midbrain axis may also exist).
phine or LY 171555 could be selectively blocked with This hypothesis was directly tested in one study [213].
pretreatment with either haloperidol or the speci®c D2 Stimulating electrodes were implanted into the region of the antagonist, spiperone, but not with the relatively selective ventromedial hypothalamus and cannula-electrodes were A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 Fig. 8. Schematic diagram indicates the proposed circuitry involved in catecholaminergic facilitation of defensive rage behavior (elicited from the ventro- medial hypothalamus). Note that an important site of interaction where catecholaminergic ®bers produced facilitation of this response is the anterior hypothalamus. Abbreviations: AH, anterior hypothalamus; AUTO, autonomic cell groups of lower brainstem; DA, dopaminergic ®bers; NE, noradrenergic ®bers; PAG, midbrain periaqueductal gray; SOM, somatic cell groups of lower brainstem; VM, ventromedial nucleus.
implanted into the medial anterior hypothalamus±preoptic induced escape, had no effect on hypothalamic aggression zone. Dopaminergic compounds were microinjected into defensive rage sites within the medial anterior hypothala- In an early study [198], systemic administration of mus±preoptic zone. In brief, microinjections of apomor- amphetamine enhanced the facilitatory effects of reticular phine or a relatively selective D2 agonist, LY 171555 (but formation stimulation upon predatory attack elicited from not a D1 agonist, SKF 38393) facilitated defensive rage (see the hypothalamus. Marini et al. [138] later demonstrated Fig. 9). Moreover, microinjections of either the non-selec- that low doses of dl-amphetamine facilitated predatory tive antagonist, haloperidol, or the D2 antagonist, sulpiride, attack and higher doses inhibited it. When catecholamine but not the D1 antagonist, SCH 23390, elevated response levels in the brain were depleted following a-methylpara- thresholds when injected alone into the anterior medial tyrosine administration, a cat's approach toward a rat was hypothalamus, and blocked the effects of apomorphine or blocked but re¯exive biting remained intact [100]. In LY 171555 when administered as a pretreatment. This result contrast, after catecholamine levels were antagonized by demonstrates that dopaminergic stimulation of the medial the dopamine b-hydroxylase (noradrenergic synthesis) anterior hypothalamus±preoptic zone facilitates defensive blocker, disul®ram, hypothalamically elicited predatory rage behavior via D2 receptors.
3.4. Noradrenergic involvement in stimulation-induced Early experiments suggested that norepinephrine facili- tates attack. However, the data were not entirely consistent.
One line of investigation [169±171] demonstrated that a selective decrease in brain norepinephrine follows defensive rage reactions produced by hypothalamic stimulation in the cat. These authors further showed that pre-collicular lesions produced recurrent defensive rage responses which were accompanied by decreases in norepinephrine content in the brainstem (in contrast to mid-collicular lesions, which were not associated with either defensive rage responses or changes in brainstem norepinephrine). The authors concluded that a fall in norepinephrine content is speci®c for defensive rage and further suggested that the central release of norepinephrine triggers the attack response.
3.4.1. Systemic injections Several investigators examined the effects of d-ampheta- mine, which causes release and prevents the reuptake of Fig. 9. Time course of the effects of microinjection of LY 171555 (50 and catecholamines, upon predatory attack and defensive rage 250 ng/0.25 ml) or vehicle (0.1% ascorbic acid) into the medial preoptico± in the cat. Amphetamine administration was reported to anterior hypothalamic area upon ventromedial-hypothalamically elicited facilitate defensive rage in one study [19], but in another hissing. Each point represents the average change in hissing threshold it had no effect upon this response when elicited from the current expressed as a percentage relative to preinjection baseline thresh- old. Arrow indicates time of injection. *p , 0.05 compared with vehicle.
medial hypothalamus [30]. In rats, systemic dl-ampheta- Bars ˆ S.E.M.; n ˆ 5 for each treatment. (From Ref. [213] with mine, at doses that affect locomotion and stimulation- A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 suppressed this response as the animals appeared lethargic and placid. In another study, Romaniuk and Golebiewski [180] microinjected norepinephrine into sites within the medial hypothalamus of the cat where carbachol could elicit defensive rage and failed to observe any changes in In more recent experiments [26, 27], whose rationale was virtually identical to that described above for Ref. [213], the underlying hypothesis was that noradrenergic ®bers modu- late neurons within the anterior medial hypothalamus.
Accordingly, infusion of noradrenergic compounds into the hypothalamus should affect hypothalamically elicited defensive rage. In brief, infusion of either norepinephrine or the a-2 agonist, clonidine, into defensive rage sites within the anterior medial hypothalamus, facilitated that response when it was elicited from the ventromedial hypothalamus.
Moreover, pretreatment with the a-2 antagonist, yohimbine, blocked the effects of both norepinephrine and clonidine. In contrast, phenylephrine (a selective a-1 agonist), proprano- lol (a b-blocking agent), terbutaline (a b-2 agonist), meto- prololartrate (a b-1 antagonist) and butoxamine (a b-2 antagonist) had little or no effect on attack when micro- injected alone or when used as a pretreatment for norepin- ephrine. Therefore, it is reasonable to conclude that the facilitating effects of norepinephrine upon defensive rage Fig. 10. Proposed model of functional relationship between amygdala, hypothalamus, and PAG with respect to the control of defensive rage beha- are mediated, in part, by actions on a-2 receptors in the vior and predatory attack behavior. Note that processes excite defensive anterior medial hypothalamus. See Fig. 8.
rage behavior by driving neurons in either the medial hypothalamus (MH) or midbrain periaqueductal gray (PAG). Because of the presence of an 3.5. The role of neuropeptides in the regulation of feline inhibitory GABAergic neuron that projects from the medial to lateral aggressive behavior hypothalamus (LH), excitation of the mechanism for defensive rage will inhibit the mechanism for predatory attack. Cholecystokinin, norepineph- 3.5.1. Opioid peptides rine, dopamine, and serotonin inputs are not shown but are important Opioid involvement in aggression is suggested by the modulators of defensive rage and predatory attack. Other abbreviations: AB, basal amygdaloid complex; AM, medial amygdaloid nucleus; CE, following evidence. First, it has been suggested, at the clin- central amygdaloid nucleus; AUTO, autonomic cell groups of lower brain- ical level, that morphine reduces heightened levels of stem; SOM, somatic cell groups of lower brainstem; EAA, excitatory amino aggressiveness [103, 104, 232]. Second, in the cat, opioid acids; ENK, enkephalin; SP, substance P; 1 , excitatory pathway; 2 , receptors and enkephalin-containing cells and axon termi- inhibitory pathway.
nals are present in dense quantities in the PAG, central attack was strongly inhibited [132]. While these studies nucleus of the amygdala, BNST, and nucleus accumbens suggest that predatory attack in the cat is facilitated by [20, 87, 89, 150, 167, 191, 192, 206].
noradrenergic mechanisms, one study conducted in the rat 3.5.1.1. Systemic studies in the cat. Three ®ndings suggest reported inhibition of hypothalamic attack after systemic that opioids selectively suppress defensive rage. First, injection of the b-blocker, propranolol [112].
systemic administration of naloxone lowered the threshold for defensive rage elicited from hypothalamus or PAG, in a 3.4.2. Intracerebral injections dose-dependent manner [50, 195]. Second, predatory attack Torda [214] induced defensive-like aggression in rats thresholds from hypothalamic sites were elevated by with the aid of foot shock and then observed that infusion naloxone administration [50], whereas thresholds for of a cocktail of norepinephrine and dopamine into the PAG-elicited contralateral circling were unaffected. Third, medial hypothalamus facilitated this response. On the ®ghting behavior induced in cats by intraventricular other hand, contrasting ®ndings were observed in another injections of carbachol was suppressed by subsequent study [84], where it was found that intraventricular infusions intraventricular injections of morphine, suggesting that m of dopamine increased shock-induced ®ghting, but norepi- receptors may be important [111].
nephrine reduced ®ghting. With respect to the cat, Mark et al. [139] induced defensive rage by placing lesions in the 3.5.1.2. Intracerebral injections in the cat. The BNST and ventromedial hypothalamus. They observed that norepi- possibly the nucleus accumbens may receive opioidergic nephrine injections into the basolateral amygdala inputs from the central nucleus of amygdala [216], and A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 Fig. 11. (a) Morphiceptin, in doses of 0.05±0.4 nmol, suppressed PAG-elicited defensive rage in a dose- and time-dependent manner; (b) pretreatment with 0.2 nmol of b-FNA 5 min prior to morphiceptin administration into the same sites blocked the suppressive effects of morphiceptin (0.05 nmol). However, pretreatment with b-FNA at a dose level of 0.05 nmol did not block the suppressive effects of either dose of morphiceptin. Bars ˆ S.E.M. (From Ref. [191] with enkephalinergic cell bodies and axon terminals are present at these sites would prevent the enkephalins from suppres- in the PAG [150].
sing the attack mechanism (see schematic diagram in Therefore, in separate experiments, the nonspeci®c enke- phalin agonist d-ala2-met5-enkephalinamide (DAME) was There also exist PAG sites which facilitate and suppress microinjected into sites within the BNST and nucleus predatory attack behavior elicited from the lateral hypotha- accumbens which modulated hypothalamically elicited lamus. These modulatory sites are in¯uenced by naloxone, defensive rage [51, 52]. At both of these nuclei, DAME suggesting that the enkephalinergic mechanism regulates elevated thresholds for modulation. Moreover, pretreatment predatory attack at the level of the PAG [229].
of these sites with naloxone blocked the effects of DAME.
At least two questions were left unanswered by these This suggests that hypothalamically elicited (or PAG- studies. The ®rst concerns the relevant subtypes of enkepha- elicited) defensive rage may be governed by an opioidergic linergic receptors, and the second relates to whether enke- input from the central nucleus, which, when activated, phalinergic neurons situated outside the PAG project suppresses defensive rage. In fact, amygdaloid inputs can directly to defensive rage sites within the PAG. These two modulate the activity of neurons in the BNST via an opioid questions were addressed in three experiments. In the ®rst mechanism [64].
experiment [194], DAME was infused into PAG defensive Two studies demonstrated that defensive rage [165] and rage sites and it was observed that thresholds increased.
predatory attack [229] are modulated within the PAG by an Pretreatment with naloxone blocked the suppressive effects opioidergic mechanism. In one study [165], defensive rage of DAME, and DAME did not affect PAG-elicited circling was elicited from the medial hypothalamus and cannula- behavior. The conclusion was that enkephalinergic recep- electrodes were placed into PAG sites which inhibited or tors in the PAG mediate suppression of defensive rage. In facilitated this response. The results indicated that infusion the second experiment, Shaikh et al. [191] sought to identify of naloxone into inhibitory, but not facilitatory, PAG sites the receptor subtypes involved in the suppression of defen- blocked the modulatory effects on hypothalamically elicited sive rage at the level of the PAG. Infusion of morphiceptin, defensive rage. Furthermore, DAME infusion into inhibi- a m agonist, into the PAG, increased thresholds for PAG- tory PAG sites inhibited hypothalamically elicited defensive elicited attack with as low a dose as 0.4 nmol. A smaller rage. These results suggest that stimulation of inhibitory increase was observed following infusion of DPDPE, a d sites in the PAG activated enkephalinergic neurons arising receptor agonist, but the k agonist U-50488H, had no effect.
from either the central nucleus of the amygdala or from Furthermore, pretreatment with m and d antagonists, b- within the PAG itself. Accordingly, infusion of naloxone Funaltrexamine (b-FNA) and ICI 174864 respectively, A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 blocked the suppressive effects of morphiceptin and DPDPE respectively, indicating the importance of these receptor subtypes (see Fig. 11).
The third experiment is as follows. It is possible that opioidergic ®bers constitute interneurons within the PAG that inhibit defensive rage when activated from an external source. Alternatively, opioid peptides may be synthesized in cell bodies located in the amygdala that project to the PAG, and, when activated, these neurons suppress defen- sive rage. In order to test this possibility, an experiment was performed. Initially, stimulation of the central or lateral nucleus produced a suppression of PAG-elicited defensive rage which lasted up to 30 min. When non-selec- tive (naloxone) and selective m (b-FNA) opioid antagonists were microinjected into PAG defensive rage sites prior to brain stimulation, the suppressive effects of amygdaloid stimulation were completely blocked (Fig. 12). However, a d antagonist (ICI 174864) had no effect. Moreover, medial amygdaloid facilitation of PAG-elicited defensive rage was unaffected by infusion of naloxone into the PAG [192]. These results suggested that the central or lateral nucleus of the amygdala suppresses defensive rage at the level of the PAG and that the probable neurotransmitter is an opioid acting upon m receptors. In order to test whether the opioid neurons were local interneurons or projection neurons from another structure, the retrograde tracer Fluoro-Gold was injected into PAG defensive rage sites.
Cells double-labeled for Fluoro-Gold and met-enkephalin immunoreactivity were found in the central nucleus and immediately adjoining regions of the lateral and basal complex. Notably, cells situated within adjoining parts of the basal complex of amygdala, which facilitate defensive rage behavior (see ®g. 21 of Ref. [201], are also double- labeled for Fluoro-Gold and aspartate or glutamate. Pend- ing further pharmacological veri®cation, this would suggest that this region of the basal complex directly facili- Fig. 12. Naloxone infusion into the PAG completely blocks the suppressive tates defensive rage behavior at the level of the PAG, effects of central amygdaloid stimulation upon PAG-elicited defensive rage utilizing excitatory amino acids as a neurotransmitter.
behavior in a dose-dependent manner. Open circles represent the time course for amygdaloid-induced suppression of defensive rage behavior as determined by the percentage change in response latencies from baseline 3.5.1.3. Opioids in the rat. As noted previously, the values obtained prior to amygdaloid stimulation. These response latencies were obtained with single stimulation of the PAG following central amyg- nonspeci®c opioid antagonist naloxone does not affect daloid stimulation. The latency values returned to baseline levels approxi- stimulation-induced attacks in the rat [112].
mately 60 min after the last trial of amygdaloid stimulation. Closed circles indicate the effects of naloxone delivery. Mean data points for each of four epochs of time (5±30, 30±60, 60±90, and 120±150 min) are represented at the beginning of each period (with permission).
3.5.2. Cholecystokinin (CCK) The neuropeptide CCK plays a role in anxiety responses. Since anxiety resembles defensive rage, in that both behaviors involve sympathetic arousal in that infusion of the CCKB antagonist into the PAG response to a threatening stimulus, one study tested the facilitated predatory attack.
effect of CCK on defensive rage in the cat [131]. Micro- injections of the CCKB agonist pentagastrin into the PAG 3.6. Amino acid neurotransmitters were found to facilitate defensive rage, whereas micro- injections of the CCKB antagonist, LY288513, but not 3.6.1. Pathways utilizing excitatory amino acids in the CCKA antagonist, PD140548, suppressed it. The speci- association with the expression or modulation of aggression ®city of this effect was demonstrated by the observation Several studies suggest that excitatory amino acids are A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 employed to test the hypothesis that the facilitatory effect of the basal complex of amygdala upon defensive rage is mediated over a pathway that projects directly to the PAG and whose functions are mediated by NMDA receptors [193]. The results showed that the facilitatory effects of basal amygdaloid stimulation could be reduced by micro- injections of AP-7 into the PAG. That this NMDA antago- nist did not block the attack response produced by single stimulation of the PAG indicates that the observed effects could not be attributed to anesthetic properties of the drug.
Moreover, this study identi®ed basal amygdaloid neurons labeled for both glutamate and Fluoro-Gold following microinjections of the retrograde tracer into attack sites in the PAG. Collectively, these ®ndings support the view that basal amygdaloid facilitation of defensive rage is mediated Fig. 13. Graphs indicate that infusion of kynurenic acid (kyn) into PAG in part by NMDA receptors over an excitatory amino acid sites, from which defensive rage behavior can be elicited, blocks the facil- pathway that projects from the basal amygdala to the PAG.
itatory effects of medial hypothalamic stimulation upon this response elicited from the PAG. This effect is dose- and time-dependent. Note that a relatively higher dose of atropine (atr) had little effect upon medial- 3.6.2. Excitatory amino acids and the elicitation of hypothalamic stimulation-induced aggression. Abbreviation: BL, theoreti- aggressive responses cal baseline values indicating the position on the graph where dual stimula- Local infusion of excitatory amino acids has been utilized tion of the medial hypothalamus has no effect in altering PAG response latencies as determined from single stimulation of the PAG. All drug doses by many investigators to demonstrate that the effects of are in nanomole values. Vertical bars indicate S.E.M. for this ®gure (with stimulation upon such events as single unit activity or auto- nomic processes were the result of activation of cell bodies rather than ®bers of passage. In recent years, this approach has been extended to the study of aggressive and related released at the terminal endings of the ®bers arising from the emotional processes with mixed success. The most effective medial hypothalamus and projecting to PAG [129, 182, region where microinjections of glutamate, aspartate or d,l- 183]. In one experiment, it was demonstrated that the homocysteic acid can elicit defensive rage behavior is the nonspeci®c excitatory amino acid antagonist, kynurenic PAG in the cat [22, 184]. However, defensive rage sites in acid, microinjected into PAG attack sites, blocked the the medial hypothalamus are not responsive to microinjec- medial hypothalamic facilitation of PAG-elicited defensive tions of excitatory amino acids. In contrast, both electrical rage, thus supporting the view that excitatory amino acids and chemical stimulation of the perifornical hypothalamus act at this synapse (Fig. 13). In additional experiments, infu- result in the elicitation of predatory attack [22]. In the squir- sion of the speci®c NMDA antagonist, AP-7, into the PAG, rel monkey, electrical and chemical stimulation can elicit blocked medial hypothalamic facilitation, whereas admini- vocalization at a number of forebrain and brainstem sites, stration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), including the lateral hypothalamus, PAG, and lateral which selectively blocks kainate and quisqualate receptors, tegmental ®elds of the brainstem [98]. It should be noted was ineffective. Moreover, infusion of NMDA into the PAG that the failure to obtain a behavioral response by micro- facilitated defensive rage elicited from the PAG, suggesting injection of an excitatory amino acid into a site where elec- that NMDA receptors mediate the effect. Parallel ®ndings trical stimulation has elicited the response does not were observed in a different experiment [182, 183]: necessarily mean that the response obtained by electrical hypothalamically elicited defensive rage was blocked stimulation was the result of stimulation of ®bers of passage.
following microinfusion of AP-7 into the PAG. Finally, Such a failure may be due to factors such as the diffuse another study combined retrograde labeling (following arrangement of cells in the region or the insensitivity of injections of Fluoro-Gold into the PAG) and immunocyto- these cells to excitatory amino acids.
chemical methods. Double-labeled cells for both Fluoro- Gold and aspartate or glutamate were found within the 3.6.3. Excitatory amino acids in the rat See Section 3.8.3.
medial hypothalamus, dorsal and somewhat rostral to the level of the ventromedial nucleus, thus demonstrating that 3.7. The role of substance P in defensive rage and predatory glutamatergic neurons project from hypothalamus to PAG.
attack in the cat These data further serve to support the notion that an exci- tatory amino acid pathway governs the input to the PAG Stimulation of the medial amygdala facilitates defensive from the medial hypothalamus for the expression of defen- rage elicited from the medial hypothalamus, but suppresses predatory attack elicited from the lateral hypothalamus In a separate study, a dual-stimulation paradigm was [201]. Moreover, the relevant projections from the medial

A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 Fig. 14. (A,C) Microinjections of the retrograde tracer Fluoro-Gold into lateral hypothalamic sites, from which predatory attack behavior could be produced, resulted in labeled cells within the medial hypothalamus, demonstrating that medial hypothalamic neurons project to the lateral hypothalamus. (B,D) Immunocytochemical staining for GABA in the same brains showed that GABA-immunopositive neurons are present in the medial hypothalamus. Arrows in A and B indicate the presence of double-labeled cells, demonstrating that GABAergic neurons project from the medial to lateral hypothalamus. C and D indicate that some neurons in the medial hypothalamus stain positively only for Fluoro-Gold and not for GABA, suggesting that not all neurons which project from medial to lateral hypothalamus are GABAergic. (From Ref. [93], with permission.) amygdala are directed through a monosynaptic pathway (i.e.
hypothalamically elicited predatory attack is also mediated, the stria terminalis) to the medial hypothalamus [48, 211].
in part, through SP receptors in the medial hypothalamus This implies that, while the effects of medial amygdaloid [92]. Speci®cally, microinjections of CP 96,345 into the stimulation upon defensive rage, which is integrated within medial hypothalamus blocked medial amygdaloid suppres- the medial hypothalamus, are direct, the effects upon sion. However, since the SP pathway mediating suppression predatory attack, which is integrated within the lateral of predatory attack terminates in the medial hypothalamus, hypothalamus, are indirect. The data presented below such modulation must require at least one additional neuron provide a likely mechanism that accounts for these effects.
for these effects to take place. The only way to account for the inhibitory action of the medial amygdala upon predatory 3.7.1. Defensive rage attack when the initial output neuron from that region is Medial amygdaloid stimulation facilitates defensive rage excitatory (i.e. an SP neuron) is to postulate the existence [48, 70, 211]. In one study, after this ®nding was replicated, of a second, inhibitory neuron that projects from the medial the SP-neurokinin 1 antagonist, CP 96,345, was micro- to the lateral hypothalamus. It was further suggested that injected into the medial hypothalamus and this was found such a neuron is likely to utilize GABA as a neurotransmit- to block the facilitating effects of medial amygdaloid ter. An experiment undertaken to test this hypothesis is stimulation [197]. Moreover, following Fluoro-Gold micro- described below [93].
injections into the medial hypothalamus, neurons labeled for both SP and Fluoro-Gold were found densely distributed 3.8. Inhibitory amino acids: GABA and glycine within the medial amygdala but not elsewhere in the temporal lobe. These observations provided evidence that 3.8.1. Defensive rage the effects of the medial amygdala upon defensive rage are GABA serves as an inhibitory neurotransmitter at many mediated via a monosynaptic pathway that acts upon SP CNS synapses. In an early study [152], GABA was injected receptors in the medial hypothalamus.
into medial hypothalamic defensive rage sites. The results, surprisingly, showed that thresholds were actually lowered 3.7.2. Predatory attack following drug infusion. In contrast, infusion of glycine into A sequel to this study, using similar methods, demon- the same sites resulted in an elevation in thresholds, indicat- strated that medial amygdaloid suppression of lateral ing a possible inhibitory role for this putative transmitter.
A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 In a later study [196] cannula-electrodes were implanted GABAA receptors in the lateral hypothalamus, where inte- into defensive rage sites within the dorsal PAG. Microinjec- gration of predatory attack occurs.
tions of the GABA agonist muscimol into defensive rage Most recently, a study [55] using a retrograde tracer and sites within the dorsal PAG produced elevations in threshold immunocytochemical labeling for GABA showed that the at as low a dose as 12 pmol. Muscimol had no effect upon inhibitory projection from medial to lateral hypothalamus is predatory attack responses elicited from ventral PAG. In matched by a reciprocal GABAergic projection from lateral addition, pretreatment with bicuculline, a GABAA to medial hypothalamus. This study also found that bicucul- antagonist, completely blocked the suppressive effects of line antagonism in the medial hypothalamus did not facili- muscimol [196]. Thus, it appears that GABA selectively tate defensive rage elicited by medial hypothalamic modulates defensive rage by serving as an inhibitory trans- stimulation alone; however, bicuculline blocked the mitter within the PAG. Nevertheless, a number of questions suppressive effects of lateral hypothalamic stimulation remain unanswered with respect to the overall role of upon defensive rage elicited by stimulation of the medial GABA in the PAG. For example, we do not know the speci- hypothalamus. The overall ®ndings of these studies are ®c receptor subtype(s) involved; nor do we know the origins summarized in Fig. 10.
of these GABA neurons. Are they local interneurons within The discovery of these reciprocal inhibitory pathways a single functional column of the PAG [23]? Or do they gives a neuroanatomical basis for the longstanding observa- originate from adjacent columns, or from distant regions tion that manipulations that inhibit defensive rage will also of the forebrain and brainstem, and speci®cally project to facilitate predatory attack, and vice versa. For example, sites within the PAG that mediate defensive rage behavior? Adamec [2±6] and Adamec and Stark-Adamec [7] observed Answers to these questions would help us understand how that limbic kindling involved, in part, neurons of origin of GABA affects defensive rage and related forms of the stria terminalis, a tract which carries ®bers from the emotional behavior.
amygdala to medial hypothalamus. Kindling of these sites caused changes in the behavioral repertoire of the catsÐ 3.8.2. Predatory attack and defensive rage: a reciprocal speci®cally, they became more defensive and less prone to inhibitory pathway between the medial hypothalamus and display predatory responses. If this kindling directly facili- lateral hypothalamus of the cat tated neuronal activity within the medial hypothalamus as a As indicated above, it was hypothesized that medial result of activation of the stria terminalis, then such excita- amygdaloid suppression of lateral-hypothalamically elicited tion would have enhanced functions associated with the predatory attack was mediated through a GABAergic medial hypothalamus, such as defensive behavior. Congru- neuron that projects from the medial to lateral hypothala- ently, the observed reduction in predatory responses may mus. To test this hypothesis [93], suppression of lateral- have been due to inhibition of the lateral hypothalamus by hypothalamically elicited predatory attack was induced activation of the short GABAergic projection from the either by electrical stimulation of the medial amygdala or by microinjection of SP into the medial hypothalamus.
Suppression of predatory attack induced by either of these 3.8.3. GABA in the rat procedures could be blocked following microinjections of Adams et al. [9] and Roeling et al. [174] gave evidence the selective GABAA antagonist, bicuculline, into the lateral for involvement of GABA receptors in hypothalamic hypothalamus. Moreover, this study also demonstrated the aggression in rats. Local infusion of the GABAA antagonist presence of GABA receptors within the lateral hypothala- bicuculline induced attacks, [174], and the GABA antago- mus as well as neurons in the medial hypothalamus that nist picrotoxin also induced aggression [9]. Most recently were labeled for both Fluoro-Gold and GABA immunoreac- Haller et al. [91] elicited aggression in the hypothalamus tivity following microinjections of the retrograde tracer into with a mixture of glutamate agonist and bicuculline applied the lateral hypothalamus (Fig. 14).
by microdialysis, but this mixture seemed to work only in The results of this study, coupled with the data described above, account for the differential effects of medial amyg- daloid stimulation on defensive rage and predatory attack.
3.9. Effects of administration of tranquilizers, In summary, the medial amygdaloid facilitation of defen- antidepressants and psychotropic drugs upon stimulation- sive rage is mediated through a monosynaptic, SP pathway induced aggressive reactions directly upon the medial hypothalamus, where integration of this form of aggression occurs. The suppressive effects of A number of investigators have attempted to determine the medial amygdala upon predatory attack are mediated how tranquilizers, antidepressants and psychotropic drugs over a disynaptic pathway. The ®rst limb of this pathway affect the aggression elicited by brain stimulation, using constitutes the (excitatory) SP projection from the medial various strategies and objectives. In one approach, aggres- amygdala to medial hypothalamus, and the second limb sive behavior is measured as part of a battery of behavioral consists of a GABAergic projection from the medial to and physiological tests in order to assess the ef®cacy of a lateral hypothalamus whose functions are mediated by number of different compounds. In this situation, the A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 principal concern is to characterize the properties of the generally increased, while predatory behavior was drugs for purposes of clinical applications. In a second suppressed. Moreover, the effects of FG-7142 upon defen- approach, drugs are employed as tools in order to study sive behavior were reversed following administration of the how speci®c transmitters affect aggression. In general, benzodiazepine antagonist, ¯umazenil. An interesting when positive results are obtained from drug tests, the feature of these studies was that they were able to show drugs are likely to appear to suppress aggression. The that FG-7142 enhanced the evoked potential in the medial primary dif®culty in interpreting such results is that it may hypothalamus resulting from basal amygdaloid stimula- not be possible to determine whether such effects are beha- tion. Assuming that this evoked potential was mediated viorally speci®c to aggression or extend to a wider range of over the stria terminalis, it is reasonable to assume that behavioral (motor) responses; few studies have addressed potentiation of this response by FG-7142 resulted from its actions upon medial and adjoining basal amygdaloid Early studies indicated that thresholds for defensive rage neurons which comprise the origin of the stria terminalis.
elicited from the medial hypothalamus of the cat are Furthermore, the differential effects of FG-7142 upon elevated following administration of antidepressants such defensive and predatory behavior can be understood in as imipramine, desimpramine and amitryptyline [30, 79].
terms of the circuitry from the medial amygdala to the It should be noted that imipramine and desimpramine also medial and lateral hypothalamus that was elaborated attenuate predatory attack responses in the cat [69]. In parti- above. Said otherwise, if FG-7142 produces its effects cular, one study [68] observed that imipramine had little or by driving neurons that comprise the origins of the stria no effect upon defensive rage in the cat and another [164] terminalis, then activation of these neurons would excite found differential dose effects: a low dose (2.5 mg/kg) medial hypothalamic neurons, which would increase the facilitated defensive rage and a higher dose (8±10 mg/kg) likelihood of occurrence of defensive rage. At the same suppressed this response. However, the clinically effective time, activation of medial hypothalamic neurons would, antidepressant ¯uvoxamine has signi®cant effects on by virtue of a GABAergic interneuron, suppress lateral hypothalamic attack in the rat [112, 118, 158].
hypothalamic neurons that mediate predatory attack.
Considerable attention has been given to the benzodiaze- Additional studies are required to identify the neuro- pine drugs, which act upon the GABA receptor complex.
physiological effects of FG-7142 treatment upon neurons Investigators have utilized chlordiazepoxide in several in the medial and basal amygdala and medial and lateral species. In the rat [162], cat [28, 79, 137] and monkey [67], peripheral administration resulted in a suppression of Ethanol, which may act upon GABA receptors, has been defensive rage and ®ghting responses. However, in the rat, a reported to affect defensive rage oppositely to the benzodia- study reported that chlordiazepoxide facilitated the occur- zepines. Speci®cally, ethanol was shown to facilitate defen- rence of quiet biting attack'' in the rat [162], whereas sive rage and suppress predatory attack in cats (Ref. [182] another study reported that it affects lateral threat more reviewed in Ref. [207]).
than biting or ®ghting [118]. It appears that, in rat, benzo- diazepines only have effects at the highest doses, where the muscle relaxant properties of these drugs are very 4. Summary and conclusions pronounced (Table 2 and Ref. [118]).
Shaikh et al. [189] observed that carbamazepine selec- The major achievements of the research carried out to tively suppressed PAG-elicited defensive rage in cats date have been to characterize the functional anatomy and while having no effect upon PAG-elicited predatory attack.
pharmacology of the synaptic regions critical for the expres- By comparison, in rats, carbamazepine has no effect on sion and modulation of aggressive responses. Of particular hypothalamic attack [118]. Similar ®ndings with respect signi®cance have been the studies in which selective to medial-hypothalamically elicited defensive rage were agonists and antagonists were administered to speci®c observed with diazepam, oxazepam [137], etizolam [78] receptor populations involved in the expression and modu- and Y-7131, an experimental drug [215]. Suppressive lation of aggression.
effects upon defensive rage were also noted for such anti- Although the anatomical relationships governing aggres- anxiety drugs as chlorpromazine and pentobarbital [30, sion in the rat have yet to be elucidated, existing data 134]. Thus, the overall effects of benzodiazepines upon suggest the presence of similarities as well as differences cat defensive rage are inhibitory, paralleling the ®ndings between the rat and cat. One similarity is that for both obtained with GABA agonists.
species, the hypothalamus seems to be critical for the Recently, a series of papers offered an alternative expression of aggressive responses; and the attack mechan- approach to the study of benzodiazepines and aggression ism seems to be powerfully modulated by different nuclei of [2, 5, 6]. These studies showed that when the anxiogenic the amygdala. Also, emerging data suggest that, for both inverse benzodiazepine agonist FG-7142 (N-methyl-b- species, serotonergic mechanisms play an inhibitory role carboline 3 carboxamide), which is a b-carboline, is in the regulation of aggression. The two species differ systemically administered to cats, defensive behavior was with respect to the organization of the response systems.
A. Siegel et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 359±389 Speci®cally, in the cat, two distinct descending pathways methods as more precise anterograde and retrograde tract from the hypothalamus to the PAG and other parts of the tracing procedures with immunocytochemistry and neuro- brainstem mediate the expression of defensive rage and pharmacology will ultimately provide us with a better predatory attack. However, in the rat, such a medial-to- means of verifying the nature of the transmitters as well lateral distinction for separate response systems is not as the origin and distribution of the pathways under inves- apparent. In addition, while the PAG is critical for the tigation. Methods for measurement of transmitter release, execution of aggression and defense in the cat, its role in such as in vivo microdialysis, should aid in clarifying the rodent aggression is unclear.
nature of the transmitters released at key synapses during That this research is relevant to human disorders is illu- the expression of an attack response. Likewise, in situ strated by the following examples. In humans, low serotonin hybridization and other histochemical methods will further has been implicated in violent murder and suicide [21, 44, help to identify the properties of neurons and neurotrans- 59±62, 181]. Moreover, recently a genetic trait in humans, mitter receptors under investigation.
associated with abnormal serotonin metabolism and person- ality disturbances including aggressive dyscontrol, has been described [47], and mimicked in mice in which the gene for monoamine oxidase A was knocked out [54]. Moreover, reuptake inhibitors of serotonin like clomipramine, ¯uoxe- This research was supported, in part, by NIH grant NS tine and ¯uvoxamine are therapeutically effective in obses- 07941-27, the Foundation of the University of Medicine and sive±compulsive disorders that escape control of the central Dentistry of New Jersey, and the Alcoholic Beverage Medi- mechanisms involved in the assessment of response appro- cal Research Foundation (to A Siegel). Another part of this priateness [168]. In addition, propranolol is effective in the study was supported by the Foundation for Biological control of pathological aggression [199], and oxazepam is Research (BION), which is subsidized by the Netherlands more effective than chlordiazepoxide in reducing feelings of Organisation for Scienti®c Research (NWO) (Grants no.
hostility in humans [127]. These pharmacological and func- 430.901P and 430.902P) to TAP Roeling and MR Kruk.
tional parallels suggest that studying the ethology, physiol- The authors wish to thank the Harry Frank Guggenheim ogy and pharmacology of hypothalamic responses may Foundation which provided separate grant support to A facilitate the understanding of the pathophysiology of Siegel and MR Kruk. The authors are indebted to Dr. KA human behavioral disorders.
Miczek, Dr. B Olivier and Dr. AM Van der Poel for their From the data presented here, it would appear that the support and review of the manuscript.
central mechanisms involved in aggression are species- speci®c to a great extent. Such species differences in aggres- sion between a highly specialized carnivorous species (i.e.
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