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S-1.-SYMPOSIUM

GLUCOCORTICOIDS AND AGGRESSION

Organizers:

Fuchs, Eberhard
Division Neurobiology, German Primate Center, Göttingen, Germany

Kruk, Menno R.
Department of  Medical Pharmacology, Leiden University, Leiden, The Nethertlands

Symposium Abstract

Data collected mainly in laboratory rodents but also in humans gave evidence that both the production and the release of adrenal glucocorticoid hormones is sufficiently fast to affect ongoing behavior. Besides their role in shaping the body to deal adequately with stressful life events, it became clear that acute glucocorticoid production at least in the case of aggressive behavior is linked to the achievement of the behavioral goal in this case winning. Since circulating glucocorticoids easily penetrate the blood-brain-barrier they interfere within specific brain areas with other neurotransmitter systems such as the monoaminergic system. Moreover, patients with disturbed aggressive control have deviant HPA-axis responses depending on the nature of their social history. The proposed symposium will bring together basic researchers and clinicians to discuss:

i) new findings on the potential role of glucocorticoids as biological trigger / marker of aggressive behavior and

ii) the underlying central nervous processes.

 

S-1.1.-DYNAMICS OF STEROIDS AND TERRITORIAL AGGRESSIVE BEHAVIOR

Haller, J., van de Schraaf*,  J. and  Kruk*, M.R.
Institute of Experimental Medicine, Budapest, Hungary. *Leiden, Amsterdam Centre for Drug Research, Leiden, The Netherlands

We have studied the effect of acute corticosterone surge on aggressive behavior in male rats. Resident rats naive to dyadic encounters have been adrenalectomized and implanted with a low release corticosterone pellet or sham operated (group C). After one week of recovery, all rats were faced in their home cage with a male intruder of smaller size. Half of the adrenalectomized rats received corticosterone ip (1mg/kg) 10 min before the encounter (group ADX-C), while the other half received only vehicle (ADX-V). Surprisingly, ADX-V rats showed significantly more aggression than both sham C and ADX-C rats. Detailed analysis of attacks revealed that ADX-V rats have attacked vulnerable parts of the body mainly (nose, throat, belly, paws), while C and ADX-C rats have targeted their attacks to less vulnerable parts of opponent's body (back, flank). In successive encounters (performed every second day), aggressiveness has increased significantly in C and ADX-C rats, while no change has occurred in the aggressiveness of ADX-V rats. In contrast to C and ADX-C rats, attacks have been persistently directed towards vulnerable parts of the opponent's body in the ADX-V group. It appears that the fight-induced acute elevation of plasma corticosterone has the role of maintaining 'normal' patterns of aggressive behavior. This finding has a striking similarity with human data showing that low variation and low level of plasma corticosterone are associated with 'deviant' forms of aggressive behavior.

S-1.2.-A DYNAMIC ADRENOCORTICAL STRESS SYSTEM IS CRUCIAL TO THE EXPRESSION OF HYPOTHALAMIC AGGRESSION

Kruk, M.R., Halasz*,  J. and Haller*, J.
Medical Pharmacology, Leiden, Amsterdam Center for Drug Research, Leiden, The Netherlands. *Institute of Experimental Medicine, Budapest, Hungary

A crucial question in the control of aggressive behaviour is how  stressors precipitate violent behaviour. In animals confronted with an adversary, plasma corticosteroids rise dramatically, even before  aggression erupts. It now appears that the aggressive area in the hypothalamus activates the adrenocortical stress response during conflict. The increasing plasma corticosteroids  rapidly cross  the blood-brain barrier, and by a positive hormonal feedback on the hypothalamic attack release mechanism (HARM) facilitates aggressive responding. Electrical or pharmacological activation of a specific area in the intermediate hypothalamus, the hypothalamic attack area (HAA) area, evokes violent attacks in otherwise peaceful animals.  Lesioning of that in that area abolish, or profoundly change aggressive behaviour. Surprisingly, minimal stimulation of HAA  produces an immediate and dramatic increase in circulating corticosterone, even in the absence of an opponent and therefore fighting. Mimicking this  response by an intra-peritoneal injection of corticosterone in animals without adrenals (ADX), facilitates hypothalamic attack within a few minutes. This facilitation closes a rapid positive feedback-loop between an aggressive brain mechanism activated via the hypothalamus and the adrenocortical stress response. Such positive feedback control would explain why sudden stressors precipitate aggressive behaviour, and why aggressive behaviour is so difficult to stop once started, or  why it so easily escalates. Long term effects of steroid hormones are caused by changes in gene expression. The rapid effects reported here are rapid and short lasting, and may be due to non-genomic effects. In animals with a low constant corticosteroid level, but with the adrenals removed before fighting experience, less than 30% of the electrodes implanted in the HAA evoke  aggression, while 65 % is the rate in intact animals. Moreover, in the 30%  that do attack, a 40% stronger stimulation is required. The latter effect is reversed by acute injections of corticosterone, but the former is not changed. These results again suggest that a dynamic adrenocortical system  is required for the behavioural expression of aggression.

S-1.3.-AGGRESSION, STRESS AND PSYCHOSTIMULANTS

Brain, P.F., Marrow*, L.N. and Overton**, P.G.
School of Biological Sciences and *Department of Psychology, University of Wales Swansea, UK. **Department of Psychology, University of Hertfordshire, UK

Encounters between Lister Hooded rats and rats of the aggressive Tryon Maze Dull strain enhance the locomotor-activating effects of cocaine in the former. This enhancement seems to arise because aggressive encounters are stressful. Stressors (e.g. electric footshock and food restriction) augment cocaine-induced behaviors. The mechanism for this action is largely unknown, but corticosterone (released during stress) appears to play an important role. It seems that corticosterone impedes the metabolism of cocaine by competing for cytochrome P-450 (CYP) 3As, involved in the oxidative metabolism of both compounds. This competitive inhibition would explain why the effects of stress on the behavioural actions of cocaine mimic exactly the effects of a higher drug dose. In support of this hypothesis, compounds which inhibit CYP 3As also enhance the locomotor-activating effects of cocaine, whilst compounds which induce CYP 3As (e.g. dexamethasone) diminish the drug’s locomotor-activating effects. This possibility, receives further support from the finding that metyrapone (which inhibits CYP 2D1) enhances both the locomotor-activating and stereotypy-inducing actions of d-amphetamine. Cytochrome P-450 2D1 is involved in the metabolism of this different psychostimulant. Although metyrapone is known to inhibit the synthesis of corticosterone, this action did not appear to play a role in our behavioural finding, since another corticosterone synthesis inhibitor (trilostane) was without effect. As stress appears an important precipitating factor in cocaine addiction, we may be one step closer to understanding the mechanism for this interaction. The fact that substances affecting CYPs can have an impact on the metabolic fate - and therefore the central actions - of psychoactive drugs is widely neglected in psychopharmacology. Since CYP 3As are involved in metabolism of hormones (e.g. testosterone) and a wide range of xenobiotics, it is crucial to assess whether manipulations which affect hormone levels also indirectly affect the responses to a given drug (and vice versa). This seems of relevance to attempts to elucidate the psychopharmacology of aggression.

S-1.4.-EFFECTS OF SUBORDINATION STRESS AND CORTISOL ON BRAIN MONOAMINE RECEPTORS

Flügge, G.
German Primate Center, Göttingen, Germany

To investigate whether stress induced behavioral changes are related to alterations in the central nervous monoamine receptor system we studied effects of chronic subordination stress on receptors in brains of male tree shrews, an established chronic psychosocial stress model. The central nervous beta-adrenoceptor system reacts quickly to stress with a transient down-regulation of beta2-adrenoceptors in the prefrontal cortex 2 days after the beginning of the stress period, and late down-regulation of beta1-adrenoceptors in the parietal cortex and the hippocampus (after 4 weeks). Alpha2-adrenoceptor are primarily down-regulated in regions that regulate autonomic functions revealing regional and stress-time dependent effects. In the locus coeruleus, down-regulation occurs already after 2 days, but in the solitary tract nucleus only after 3 weeks.  Since alpha2-adrenoceptors in the locus coeruleus neurons function as autoreceptors, reduced receptor numbers might be a reason for the hyperactivity of the noradrenergic system during periods of chronic stress. Reactions of the serotonergic system occur later than those of the noradrenergic system with reduced 5HT1A-receptor numbers after 10 days of subordination stress in the occipital cortex, and after 4 weeks in the hippocampus. To investigate whether the stress effects are due to the hyperactivity of the HPA-axis, we treated male tree shrews with cortisol. Two experiments were performed: a short-term treatment (males were injected i.v. with 1.5 mg cortisol and brains were dissected 2 hr later), and a long-term treatment (cortisol was applied via drinking water during 5 days; daily uptake 3-7 mg). The short-term treatment, similar to the stress, down-regulated alpha2-adrenoceptors. In contrast, the long-term oral treatment induced regional alpha2-adrenoceptor up-regulation. However, cortisol effects on 5HT1A-receptor binding were the same as those of chronic stress. These data (I) show that glucocorticoids regulate monoamine receptors in the brain, (ii) that the duration and/or the route of cortisol application determines the results, and (iii) indicate that chronic stress effects on monoamine receptors are not only due the long-term glucocorticoid exposure but also to other components of the stress response.  (Supported by DFG, SFB 406).

S-1.5.-ALTERATIONS IN THE HYPOTHALMUS PITUITARY ADRENAL AXIS AND SEROTONERGIC SYSTEM IN IMPULSIVE AND AGGRESSIVE FEMALE BORDERLINE PERSONALITY DISORDER PATIENTS

Rinne, T.
Psychiatric Hospital "
De Geestgronden",  Bennebroek, The Netherlands

Patients with borderline personality disorder (BPD) are characterized by symptoms of affect- and impuls-dysregulation, as well as aggressive and auto-aggressive behavior, features which are all associated with alterations of the serotonergic system (5-HT system). This group of patients has often experienced sustained traumatic stress at young age.  Traumatic stress leads to disturbances of the complex neuro-endocrine feed back mechanisms results in  changes of the hypothalmus pituitary adrenal axis (HPA-axis) and the monoamine systems. To investigate alterations in serotonergic system and HPA axis in relation to early traumatisation we performed two neuroendocrine challenge studies one with the 5HT agonist m-chlorophenylpiperazine (m-CPP) in 12 female BPD patients and the second with a combined dexamethason /corticotropin-releasing-hormon-test (DEX/CRH) in 41 female borderline patients. In both studies the challenge studies were repeated after 8 respectively 12 weeks of treatment with the selective serotonine reuptake inhibitor fluvoxamine to investigate whether SSRI treatment restores the probable alterations of the 5-HT system and the HPA-axis and whether this restoration is correlated with clinical improvement. The cortisol and prolactin response to the m-CPP challenge in BPD patients were significantly blunted. The prolactin blunting was highly inversly correlated with sustained childhood abuse. The SSRI treatment had no effect on the blunted cortisol and prolactin responses despite clinical significant improvements. This suggest that these responses are more trait than state depended and that the prolactin blunting is independend of BPD diagnosis and more likely to be a trauma marker.  Preliminary data from 9 patients of the DEX/CRH study suggest that the traumatized BPD patients exhibit a significant higher afternoon cortisol plasma level compared to the not traumatized patients. All patients show suppression to dexamethason. After i.v. CRH injection cortisol and ACTH are significantly enhanced except in patients with a  posttraumatic stress disorder. After SSRI treatment ACTH and cortisol plasma levels enhancement is significantly reduced compared to the first test.