Menno R. Kruk

Neuropharmacology of brain-stimulation-evoked aggression.

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, norepinephrine, 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 significant 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.

Genomic and non-genomic effects of glucocorticoids on aggressive behavior in male rats.

An increasing body of evidence suggests that glucocorticoids--besides their well-known genomic effects--can affect neuronal function via mechanisms that do not involve the genome. Data obtained mainly in amphibians and birds suggest that such mechanisms play a role in the control of behavior. Acute glucocorticoid treatments increase aggressive behavior in rats, but the mechanism of action has not been investigated to date. To clarify the issue, we have assessed the aggressiveness of male rats after treating them with the corticosterone synthesis inhibitor metyrapone, corticosterone, and the protein synthesis inhibitor cycloheximide. Metyrapone applied intraperitoneally (i.p.) decreased the aggressiveness of residents faced with smaller opponents. Corticosterone administered i.p. 20 or 2 min before a 5-min encounter abolished these changes irrespective of the delay of behavioral testing. Thus, the effects of glucocorticoids on aggressive behavior occurred in less than 7 min (the delay and duration of testing taken together), and lasted more than 25 min. Corticosterone applied centrally (infused into the right lateral ventricle) also stimulated aggressive behavior rapidly, which shows that the effect was centrally mediated. The protein synthesis inhibitor cycloheximide did not affect the aggression-promoting effects of corticosterone when the hormone was injected 2 min before the aggressive encounter. Surprisingly, however, the effects were completely abolished when the hormone was injected 20 min before the encounter. These data suggest that glucocorticoids rapidly increase aggressive behavior via non-genomic mechanisms. In later phases of the aggressive encounter, aggressive behavior appears to be stimulated by genomic mechanisms.

Fast positive feedback between the adrenocortical stress response and a brain mechanism involved in aggressive behavior.

Aggressive behavior induces an adrenocortical stress response, and sudden stressors often precipitate violent behavior. Experiments in rats revealed a fast, mutual, positive feedback between the adrenocortical stress response and a brain mechanism controlling aggression. Stimulation of the aggressive area in the hypothalamus rapidly activated the adrenocortical response, even in the absence of an opponent and fighting. Hypothalamic aggression, in turn, was rapidly facilitated by a corticosterone injection in rats in which the natural adrenocortical stress response was prevented by adrenalectomy. The rapidity of both effects points to a fast, mutual, positive feedback of the controlling mechanisms within the time frame of a single conflict. Such a mutual facilitation may contribute to the precipitation and escalation of violent behavior under stressful conditions.

Effect of environmental stressors on time course, variability and form of self-grooming in the rat: Handling, social contact, defeat, novelty, restraint and fur moistening

Grooming is often related to dearousal following stressors. Interestingly, electrical and chemical stimulation of the paraventricular nucleus of the hypothalamus (PVH), at levels that are known to activate the hypothalamus-pituitary adrenal axis (HPA), also elicits grooming. At the level of the PVH, the neuroendocrine stress response is apparently still linked to the behavioural response to stressors. However the precise nature of this relation is not fully understood. Here we report on grooming in rats following exposure to different stressors which are known to activate the HPA axis. Stressors such as handling, restraint, novelty, encounters with aggressive or non-aggressive conspecifics, or moistening the fur, change the amount and time course of grooming upon return in the home cage, as compared with controls that are just handled. However, the amount of grooming is not directly related to the strength of the stressor. Defeated intruders groom less upon return in their home cage. Novelty and non-aggressive encounters with conspecifics reduce the variation in the amount of grooming between rats. The time course of grooming over the 20-min observation period also differs between treatments. Following restraint, or exposure to non-aggressive conspecifics, grooming first increases and then decreases. Moistened rats immediately start grooming which subsequently decreases. Rats used as intruders in the territory of another rat maintain a constant low level of grooming. Rats placed in a novel cage steadily increase grooming during the 20-min observation period. These results suggest that grooming cannot be simply understood as an immediate response necessary to reduce arousal following stressors. Following exposure to a stressor, grooming rather seems temporary suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamic substrates for brain stimulation-induced attack, teeth-chattering and social grooming in the rat.

In this paper the boundaries of the hypothalamic response areas for brain stimulation-induced attack, social grooming and teeth-chattering were delimited. A total of 641 hypothalamic sites in 71 male CPW/WU Wistar rats were electrically stimulated. Positive sites for any behavioural response cluster into restricted hypothalamic areas. Discriminant analysis of both positive and negative electrode localizations yields areas with high, intermediate and low probabilities of inducing the behavioural response concerned. Each response has its own response area where probabilities are high. Neuroanatomical correlates of these response areas are discussed. The response area of attack is suggested to be an integrative processing area, stimulation of which overrules some aspects of integration and directly activates the behavioural program of attack. Although some authors consider all three responses to be part of the behavioural repertoire of aggression, the response areas are not identical. Social grooming and attack are considered to be induced from different neural systems. Similarly, attack and teeth-chattering have been shown to derive from different neural mechanisms, despite substantial overlap of both response areas. It is suggested that teeth-chattering derives from the simultaneous activation of both attack and flight tendencies. No further distinctions with respect to threshold current intensities can be made within responses areas. However, the underlying neural substrates are not homogeneous, for thresholds vary along the course of individual electrodes.

Hypothalamic substrates for brain stimulation-induced patterns of locomotion and escape jumps in the rat

The hypothalamic response area for electrically induced locomotion was determined using moveable electrodes and discriminant analysis as an appropriate statistical technique. At 241 out of 641 stimulated sites locomotion was induced. The distribution of locomotion sites is relatively diffuse. Discriminant analysis of both positive and negative electrode localizations yields areas with high, intermediate or low probability of inducing the response. The response is considered to be mediated by fibres of the subpallido-pedunculopontine system, which includes the mesencephalic locomotor region. Different categories of exploratory and flight-directed locomotion were distinguished, and response areas for both categories were determined. In addition the response area for escape jumps was delimited. Exploratory locomotion is mainly induced from the lateral hypothalamus, while flight-directed locomotion and escape jumps are evoked from the medial hypothalamus. The response area for exploratory locomotion reflects the lateral hypothalamic distribution of the subpallidal projection to the mesencephalic locomotor region. A diffuse substrate for flight behavior seems to occupy almost the entire medial hypothalamus. It is concluded that a locomotor subroutine subserving different behavioural mechanisms can be activated at many hypothalamic sites.

Chronic glucocorticoid deficiency-induced abnormal aggression, autonomic hypoarousal, and social deficit in rats

Certain aggression‐related psychopathologies are associated with decreased glucocorticoid production and autonomic functions in humans. We have previously shown that experimentally‐induced chronic glucocorticoid deficiency leads to abnormal forms of attack in rats. Here, we compared the effects of acute and chronic glucocorticoid deficiency on aggressive behaviour, autonomic responses to challenges, and anxiety. Glucocorticoid synthesis was blocked acutely by the glucocorticoid synthesis blocker metyrapone or chronically by adrenalectomy and low glucocorticoid replacement (ADXr). As shown previously, chronic glucocorticoid deficiency facilitated aberrant attacks directed towards the most vulnerable parts of the opponents body. The acute inhibition of glucocorticoid synthesis lowered aggressive behaviour without affecting attack targeting. In a different experiment, ADXr rats and their sham‐operated controls were exposed to different challenges whereas their heart rate and locomotion were telemetrically recorded. Autonomic responses to social challenges were lowered by chronic, but not by acute glucocorticoid deficiency. Autonomic responses to the elevated plus‐maze were only slightly affected by chronic glucocorticoid deficiency. Locomotor behaviour was not affected in either challenge; thus, the altered autonomic reactions were not due to interference from workload. The behaviour of ADXr rats was similar to that of sham‐operated controls in the elevated plus‐maze, but ADXr rats showed reduced social interactions in the social interaction test. Our data demonstrate that, in rats, chronic but not acute glucocorticoid deficiency induces abnormal attack patterns, deviant cardiovascular responses and social deficits that are similar to those seen in abnormally violent humans. Thus, the similar correlations found in humans probably cover a causal relationship. Experimentally‐induced glucocorticoid deficiency may be used to assess the mechanisms underlying glucocorticoid deficiency‐induced abnormal forms of aggressiveness.

Acute effects of glucocorticoids: behavioral and pharmacological perspectives

There has been evidence since the early eighties that glucocorticoids, apart from their well known chronic effects, may have acute, short-term effects. However, a lack of understanding of the molecular mechanisms of action has hampered appreciation of these observations. Mounting evidence over the years has continued to confirm the early observations on a fast corticosterone control of acute behavioral responses. We summarize experimental data obtained mainly in rats but also in other species which show: (1) that glucocorticoid production is sufficiently quick to affect ongoing behavior; (2) that there exist molecular mechanisms that could conceivably explain the fast neuronal effects of glucocorticoids (although these are still insufficiently understood); (3) that glucocorticoids are able to stimulate a wide variety of behaviors within minutes; and (4) that acute glucocorticoid production (at least in the case of aggressive behavior) is linked to the achievement of the behavioral goal (winning). The achievement of the behavioral goal reduces glucocorticoid production. It is argued that glucocorticoids are regulatory factors having a well-defined behavioral role. Both the acute (stimulatory) effects and the chronic (inhibitory) effects are adaptive in nature. The acute control of behavior by corticosterone is a rather unknown process that deserves further investigation. The pharmacologic importance of the acute glucocorticoid response is that it may readily affect the action of pharmacologic agents. An interaction between acute glucocorticoid increases and noradrenergic treatments has been shown in the case of offensive and defensive agonistic behavior. Non-behavioral data demonstrate that acute increases in glucocorticoids may interfere with other neurotransmitter systems (e.g., with the 5HT system) as well. These observations show the importance of taking into account endocrine background and endocrine responsiveness in behavior pharmacological experiments.

Neural background of glucocorticoid dysfunction‐induced abnormal aggression in rats: involvement of fear‐ and stress‐related structures

Glucocorticoid hypofunction is associated with persistent aggression in some psychologically disordered human subjects and, as reported recently, induces abnormal forms of aggression in rats. Here we report on the effects of glucocorticoid hypofunction on aggression‐induced neural activation. Rats were adrenalectomized, and implanted with low‐release glucocorticoid pellets. After one week recovery, they were challenged by an unfamiliar intruder in their home‐cage. Neural activation was studied by c‐Fos protein immunocytochemistry. Aggressive encounters in controls induced c‐Fos activation in all brain areas relevant for the control of aggression (cortex, amygdala, septum, hypothalamus, periaqueductal grey and the locus coeruleus). Very intense c‐Fos activation was observed in the medial amygdala, the hypothalamic attack area and the periaqueductal grey matter which constitute a downward stimulatory stream that activates attack behaviour. The experimentally induced glucocorticoid hypofunction dramatically increased attacks targeted towards vulnerable parts of the opponents body (mainly the head). This abnormal behaviour was not associated with changes in the activation of brain centres involved in the control of aggression. However, the activation of brain centres involved in both the stress response (the parvocellular part of the hypothalamic paraventricular nucleus) and fear reactions (central amygdala) were markedly increased. An acute glucocorticoid treatment abolished both behavioural and neural consequences of glucocorticoid hypofunction. Our data suggest that glucocorticoid hypofunction‐induced abnormal forms of aggressiveness are related to increased sensitivity to stressors and fear‐eliciting stimuli. This assumption is supported by the finding that fearful situations induce attack patterns in intact rats that are similar to those induced by glucocorticoid hypofunction.

The hypothalamus: cross-roads of endocrine and behavioural regulation in grooming and aggression

Anatomical and functional studies show that the hypothalamus is at the junction of mechanisms involved in the exploratory appraisal phase of behaviour and mechanisms involved in the execution of specific consummatory acts. However, the hypothalamus is also a crucial link in endocrine regulation. In natural settings it has been shown that behavioural challenges produce large and fast increases in circulating hormones such as testosterone, prolactin, corticotropin and corticosterone. The behavioural function and neural mechanisms of such fast neuroendocrine changes are not well understood. We suggest that behaviourally specific hypothalamic mechanisms, at the cross-roads of behavioural and endocrine regulation, play a role in such neuroendocrine changes. Mild stimulation of the hypothalamic aggressive area, produces stress levels of circulating prolactin, corticotropin, and corticosterone. Surprisingly luteinizing hormone does not change. This increase in stress hormones is due to the stimulation itself, and not caused by the stress of fighting. Similar increases in corticosterone are observed during electrical stimulation of the hypothalamic self-grooming area. The corticosterone response during self-grooming-evoking stimulation is negatively correlated with the amount of self-grooming observed, suggesting that circulating corticosterone exerts a negative feedback control on grooming. Earlier literature, and preliminary data form our laboratory, show that circulating corticosterone exerts a fast positive feedback control over brain mechanisms involved in aggressive behaviour. Such findings suggest that the hormonal responses caused by the activity of behaviourally specific areas of the hypothalamus may be part of a regulation mechanism involved in facilitating or inhibiting the very behavioural responses that can be evoked from those areas. We suggest that studying such mechanisms may provide a new approach to behavioural dysfunctions associated with endocrine disorders and stress.