Enhanced sensitivity of postsynaptic serotonin-1A receptors in rats and mice with high trait aggression

Individual differences in aggressive behaviour have been linked to variability in central serotonergic activity, both in humans and animals. A previous experiment in mice, selectively bred for high or low levels of aggression, showed an up-regulation of postsynaptic serotonin-1A (5-HT1A) receptors, both in receptor binding and in mRNA levels, in the aggressive line. The aim of this experiment was to study whether similar differences in 5-HT1A receptors exist in individuals from a random-bred rat strain, varying in aggressiveness. In addition, because little is known about the functional consequences of these receptor differences, a response mediated via postsynaptic 5-HT1A receptors (i.e., hypothermia) was studied both in the selection lines of mice and in the randomly bred rats. The difference in receptor binding, as demonstrated in mice previously, could not be shown in rats. However, both in rats and mice, the hypothermic response to the 5-HT1A agonist alnespirone was larger in aggressive individuals. So, in the rat strain as well as in the mouse lines, there is, to a greater or lesser extent, an enhanced sensitivity of postsynaptic 5-HT1A receptors in aggressive individuals. This could be a compensatory up-regulation induced by a lower basal 5-HT neurotransmission, which is in agreement with the serotonin deficiency hypothesis of aggression.

Development of violence in mice through repeated victory along with changes in prefrontal cortex neurochemistry

Recent reviews on the validity of rodent aggression models for human violence have addressed the dimension of pathological, maladaptive, violent forms of aggression in male rodent aggressive behaviour. Among the neurobiological mechanisms proposed for the regulation of aggressive behaviour in its normal and pathological forms, serotonin plays a major role. However, the results on the detailed mechanism are still confusing and controversial, mainly because of difficulties in extrapolating from rodent to human psychopathological behaviour. Our aim was to investigate the involvement of serotonin in pathological aggression. We subjected mice genetically selected for high (SAL, TA, NC900 lines) and low (LAL, TNA, NC100) aggression levels to a repeated resident-intruder experience (RRI mice) or to handling as a control procedure (CTR mice). Pathological aggression parameters we recorded were aggression towards females and lack of communication between the resident and its opponent. In the same mice, we measured the monoamine levels in the prefrontal cortex, a brain region strongly involved in the regulation of motivated behaviour. Our results show that SAL mice augmented their proneness to attack and showed the most pathological phenotype, with disregard of the opponent's sex, high territorial behavioural patterns, and low sensitivity to signals of subordination. In contrast, TA and NC900 augmented their proneness to attack and low discrimination of the opponent's signals, without showing offence towards females. After repeated resident-intruder experience, serotonin levels in the prefrontal cortex were significantly lower in SAL than in LAL whereas dopamine turnover was significantly higher, compared to CTR mice. Serotonin turnover was significantly reduced in all RRI mice, with no strain differences. Noradrenaline was significantly lower in aggressive mice of the TA and NC900 lines compared to their low-aggressive counterparts, with no effect of the repeated resident-intruder experience. We conclude that social experience changes prefrontal cortex neurochemistry and elicits pathologically aggressive phenotypes. (C) 2008 Elsevier B.V. All rights reserved

Does the current concept of stress explain PTSD

Understanding the etiology of stress-related diseases such as PTSD requires a more fundamental understanding of stress. Since individuals may differ strongly in their response to a stressor, it is argued that stress includes not only the stimulus and the response but also the individual appraisal of the situation. This chapter discusses the stress concept, how it has evolved in the course of time, and some important components of the appraisal process. In addition to the factors controllability and predictability, outcome expectancy and feedback of the victim’s own actions during the traumatic event are suggested to be important factors in the development of stress-related disease. Preliminary preclinical studies suggest that individual differences in the way in which these factors are used in the appraisal of everyday life situations may explain individual vulnerability

Temporal and spatial dynamics of corticosteroid receptor down-regulation in rat brain following social defeat

The experiments explored the nature and time course of changes in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) binding in homogenates of various brain regions and pituitary of male Wistar rats following social defeat stress. One week after defeat, the binding capacity of GRs was decreased in the hippocampus and the hypothalamus while no changes were observed in the parietal cortex and the pituitary. The number of MRs remained at the same level as in undefeated rats. Three weeks postdefeat, the initially down-regulated GR returned to baseline level in the hippocampus and the hypothalamus. However, GR binding was now decreased in the parietal cortex. Severe down-regulation of MRs was detected in the hippocampal and septal tissue. The results show that brief but intense stress like social defeat induces a long-lasting down-regulation of corticosteroid receptors and that the temporal dynamics of these changes are not only differential for GRs and MRs but also for brain sites.

The Vicious Cycle Towards Violence: Focus on the Negative Feedback Mechanisms of Brain Serotonin Neurotransmission

Violence can be defined as a form of escalated aggressive behavior that is expressed out of context and out of inhibitory control, and apparently has lost its adaptive function in social communication. Little is known about the social and environmental factors as well as the underlying neurobiological mechanisms involved in the shift of normal adaptive aggression into violence. In an effort to model the harmful acts of aggression and violence in humans, we recently (re)developed an animal model that is focused on engendering uncontrolled forms of maladaptive aggressive behavior in laboratory-bred feral rats and mice. We show that certain (8–12%) constitutionally aggressive individuals gradually develop, over the course of repetitive exposures to victorious social conflicts, escalated (short-latency, high-frequency and ferocious attacks), persistent (lack of attack inhibition by defeat/submission signals and perseverance of the aggressive attack-biting bout), indiscriminating (attacking female and anesthetized male intruders) and injurious (enhanced vulnerable-body region attacks and inflicted wounding) forms of offensive aggression. Based on the neurobiological results obtained using this model, a revised view is presented on the key role of central serotonergic (auto)regulatory mechanisms in this transition of normal aggression into violence

Possible lack of full cross-resistance of 5HT3 antagonists; a pilot study

We investigated the potential of cross-over to the serotonin receptor (5HT3) antagonist ondansetron after protection failure with tropisetron. Several cases of complete protection were observed. These limited data suggest that there is an indication for retreatment with a different 5HT3 antagonist after an initial failure to another and also stress the need and relevance for comparative studies between 5HT3 antagonists

The accuracy and timing of pedestrian warnings at intersections: the acceptance from drivers and their preferences

The safety of vulnerable road users at traffic intersections is critical. Driver assistance systems can improve safety but have to rely on accurate detection of hazardous situations. Given the complexity of pedestrian movement, detection of pedestrian presence and prediction of their behaviour are not always without error. Drivers' attitude towards such errors is an important issue for the effectiveness of the system. An online questionnaire survey has been carried out to investigate drivers' acceptance of the system under different reliability and accuracy configurations. The results show that safety warnings of pedestrians are generally found to be useful, although false positives and false negatives tend to reduce its pleasantness. The system is found to be most useful for right turn movement at a busy intersection, compared to through movements and quiet intersections. Drivers also find false alarms more acceptable than false negatives. In terms of timing of the warning message, drivers prefer to receive it earlier rather than later

Selection by AZT and Rapid Replacement in the Absence of Drugs of HIV Type 1 Resistant to Multiple Nucleoside Analogs

We studied the intrahost evolution and dynamics of a multidrug-resistant HIV-1, which contains an insertion of two amino acids (aa) and several aa changes within the reverse transcriptase (RT) gene. From an individual receiving intermittent therapy, sequences of 231 full-length molecular clones of HIV-1 RT were obtained from serum-derived viruses at 12 consecutive time points over a period of 6 years, 17 to 20 clones per time point. In the 3.5-year period prior to the first course of therapy, only wild-type (wt) viruses were found. As soon as 6 months after the start of zidovudine (AZT) monotherapy, all viruses contained an insertion of two aa between positions 68 and 69 of the RT and aa changes at positions 67 and 215, a combination conferring resistance to multiple nucleoside analogs. After termination of therapy, the insertion mutants were rapidly and completely replaced by the wt viruses. In turn, the insertion mutants replaced the wt viruses after initiation of therapy with 3TC, d4T, and saquinavir. After termination of triple therapy, the wt viruses completely replaced the mutants within 1 month, which is markedly faster than has been observed earlier for the replacement of AZT-resistant viruses. Fast replacements of the mutant virus populations after termination of therapy indicate gross competitive disadvantage of the insertion mutant in the absence of therapy, which we estimated by using several models. The insertion mutants attained high virus loads, demonstrating that virus load cannot be used as a direct measure of virus fitness