Neuroendocrinology of coping styles: towards understanding the biology of individual variation.

Individual variation in behavior and physiology is a widespread and ecologically functional phenomenon in nature in virtually all vertebrate species. Due to domestication of laboratory animals, studies may suffer from a strong selection bias. This paper summarizes behavioral, neuroendocrine and neurobiological studies using the natural individual variation in rats and mice. Individual behavioral characteristics appear to be consistent over time and across situations. The individual variation has at least two dimensions in which the quality of the response to a challenging condition (coping style) is independent from the quantity of that response (stress reactivity). The neurobiology reveals important differences in the homeostatic control of the serotonergic neuron and the neuropeptides vasopressin and oxytocin in relation to coping style. It is argued that a careful exploitation of the broad natural and biologically functional individual variation in behavior and physiology may help in developing better animal models for understanding individual disease vulnerability.

Is hyper-aggressiveness associated with physiological hypoarousal? A comparative study on mouse lines selected for high and low aggressiveness.

Aggressiveness is often considered a life-long, persistent personality trait and is therefore expected to have a consistent neurobiological basis. Recent meta-analyses on physiological correlates of aggression and violence suggest that certain aggression-related psychopathologies are associated with low functioning of the hypothalamo-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). We tested this hypothesis in mice selected for high and low aggressiveness by measuring baseline plasma corticosterone levels and, via radiotelemetry, heart rate and core body temperature. The radiotelemetric recordings were made for 48 h under baseline undisturbed conditions and for 90 min after a handling stressor. Consistent with the hypoarousal hypothesis of violence, we found lower resting heart rates in two out of the three highly aggressive selection lines. In contrast, body temperature during the active phase, as another ANS-regulated physiological parameter, was higher in two out of three highly aggressive lines. The handling-induced tachycardiac and hyperthermic responses were similar across the six mouse lines except for the most docile and obese line, which showed a blunted reactivity. Besides significant differences between strains, no differences in plasma corticosterone levels were found between the high- and low-aggressive phenotypes. These results are discussed in relation to the different types of aggression (normal versus pathological) exhibited by the three highly aggressive lines. We conclude that while high trait-like aggressiveness is generally associated with a higher active phase core body temperature, only animals that express pathological forms of aggression are characterized by a low resting heart rate.

Social stress models in rodents: Towards enhanced validity.

Understanding the role of the social environment in the development of stress related diseases requires a more fundamental understanding of stress. Stress includes not only the stimulus and the response but also the individual appraisal of the situation. The social environment is not only essential for survival it is at the same time an important source of stressors. This review discusses the social stress concept, how it has been studied in rodents in the course of time and some more recent insights into the appraisal process. In addition to the factors controllability and predictability, outcome expectancy and feedback of the victim's own actions during the social stress are suggested to be important factors in the development of stress related disease. It is hypothesized that individual differences in the way in which these factors are used in the appraisal of everyday life situations may explain individual vulnerability.

Patterns of violent aggression-induced brain c-fos expression in male mice selected for aggressiveness.

Mice selected for aggressiveness (long and short attack latency mice; LALs and SALs, respectively) constitute a useful tool in studying the neural background of aggressive behavior, especially so as the SAL strain shows violent forms of aggressiveness that appear abnormal in many respects. By using c-Fos staining as a marker of neuronal activation, we show here that agonistic encounters result in different activation patterns in LAL and SAL mice. In LALs, agonistic encounters activated the lateral septum, bed nucleus of stria terminalis, medial amygdala, paraventricular nucleus of the hypothalamus, anterior hypothalamic nucleus and tuber cinereum area (both being analogous with the rat hypothalamic attack area), dorsolateral periaqueductal gray, and locus coeruleus. This pattern is similar with that seen in the territorial aggression of male mice, rats and hamsters, and non-lactating female mice. SALs showed strong fight-induced activations in the central amygdala and lateral/ventrolateral periaqueductal gray. In this strain, no activation was seen in the lateral septum and the dorsolateral periaqueductal gray. This pattern is similar with that seen in other models of violent aggression, e.g., in attacks induced by hypothalamic stimulation in rats, quiet biting in cats, lactating female mice, and hypoarousal-driven abnormal aggression in rats. We suggest here that the excessive activation of the central amygdala and lateral/ventrolateral periaqueductal gray--accompanied by a smaller activation of the septum and dorsolateral periaqueductal gray--underlay the expression of violent attacks under various circumstances.

Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats.

The CNS melanocortin (MC) system is implicated as a mediator of the central effects of leptin, and reduced activity of the CNS MC system promotes obesity in both rodents and humans. Because activation of CNS MC receptors has direct effects on autonomic outflow and metabolism, we hypothesized that food intake-independent mechanisms contribute to development of obesity induced by pharmacological blockade of MC receptors in the brain and that changes in hypothalamic neuropeptidergic systems known to regulate weight gain [i.e., corticotropin-releasing hormone (CRH), cocaine-amphetamine-related transcript (CART), proopiomelanocortin (POMC), and neuropeptide Y (NPY)] would trigger this effect. Relative to vehicle-treated controls, third intracerebroventricular (i3vt) administration of the MC receptor antagonist SHU9119 to rats for 11 d doubled food and water intake (toward the end of treatment) and increased body weight ( approximately 14%) and fat content ( approximately 90%), hepatic glycogen content ( approximately 40%), and plasma levels of cholesterol ( approximately 48%), insulin ( approximately 259%), glucagon ( approximately 80%), and leptin ( approximately 490%), whereas spontaneous locomotor activity and body temperature were reduced. Pair-feeding of i3vt SHU9119-treated animals to i3vt vehicle-treated controls normalized plasma levels of insulin, glucagon, and hepatic glycogen content, but only partially reversed the elevations of plasma cholesterol ( approximately 31%) and leptin ( approximately 104%) and body fat content ( approximately 27%). Reductions in body temperature and locomotor activity induced by i3vt SHU9119 were not reversed by pair feeding, but rather were more pronounced. None of the effects found can be explained by peripheral action of the compound. The obesity effects occurred despite a lack in neuropeptide expression responses in the neuroanatomical range selected across the arcuate (i.e., CART, POMC, and NPY) and paraventricular (i.e., CRH) hypothalamus. The results indicate that reduced activity of the CNS MC pathway promotes fat deposition via both food intake-dependent and -independent mechanisms.

The neurobiology of offensive aggression: Revealing a modular view.

Experimental studies aimed at understanding the neurobiology of aggression started in the early 20th century, and by employing increasingly sophisticated tools of functional neuroanatomy (i.e., from electric/chemical lesion and stimulation techniques to neurochemical mapping and manipulations) have provided the important framework for the functional brain circuit organization of aggressive behaviors. Recently, newly emerging technologies for mapping,measuring and manipulating neural circuitry at the level of molecular and genetically defined neuronal subtypes promise to further delineate the precise neural microcircuits mediating the initiation and termination of aggressive behavior, and characterize its dynamic neuromolecular functioning. This paper will review some of the behavioral, neuroanatomical and neurochemical evidence in support of a modular view of the neurobiology of offensive aggressive behavior. Although aggressive behavior likely arises from a specific concerted activity within a distributed neural network across multiple brain regions, emerging opto- and pharmacogenetic neuronal manipulation studies make it clear that manipulation of molecularly-defined neurons within a single node of this global interconnected network seems to be both necessary and sufficient to evoke aggressive attacks. However, the evidence so far also indicates that in addition to behavior-specific neurons there are neuronal systems that should be considered as more general behavioral control modules. The answer to the question of behavioral specificity of brain structures at the level of individual neurons requires a change of the traditional experimental setup. Studies using c-fos expression mapping usually compare the activation patterns induced by for example aggression with a home cage control. However, to reveal the behavioral specificity of this neuronal activation pattern, a comparison with other social and non-social related behaviors such as mating, defensive burying or running might be more appropriate. In addition, the correlations between aggressive behavior and other behaviors in different environmental contexts might give an indication of these more general behavioral control functions. Elucidating how neural circuits that modulate social-aggressive behavior also mediate other complex emotional behaviors or states will lead to a better understanding of the molecular mechanisms by which social deficits are expressed in various neuropsychiatric disorders. This likely will lead to more efficacious pharmacological or circuit-based therapeutics to curb excessive/abnormal aggressive behavior and improve social function.

The temporal dynamics of the stress response.

This paper summarises the available evidence that failure of defense mechanisms in (semi)-natural social groups of animals may lead to serious forms of stress pathology. Hence the study of social stress may provide animal models with a high face validity. However, most of the animal models of human stress-disorders have concentrated on the consequences of chronic exposure to stressors. The present paper considers recent data, indicating that a single experience with a major stressor in the form of social defeat may have long-term consequences ranging from hours to days and weeks. It seems that the experience of a major stressor sensitizes the animal to subsequent stressors. The consequences of these long-term temporal dynamics of the stress response to the development of stress-related disorders and stress-vulnerability are discussed.

Coping styles in animals: current status in behavior and stress-physiology.

This paper summarizes the current views on coping styles as a useful concept in understanding individual adaptive capacity and vulnerability to stress-related disease. Studies in feral populations indicate the existence of a proactive and a reactive coping style. These coping styles seem to play a role in the population ecology of the species. Despite domestication, genetic selection and inbreeding, the same coping styles can, to some extent, also be observed in laboratory and farm animals. Coping styles are characterized by consistent behavioral and neuroendocrine characteristics, some of which seem to be causally linked to each other. Evidence is accumulating that the two coping styles might explain a differential vulnerability to stress mediated disease due to the differential adaptive value of the two coping styles and the accompanying neuroendocrine differentiation.

Somatodendritic 5-HT(1A) autoreceptors mediate the anti-aggressive actions of 5-HT(1A) receptor agonists in rats: an ethopharmacological study with S-15535, alnespirone, and WAY-100635.

To elucidate the relative contribution of somatodendritic 5-HT(1A) autoreceptors and postsynaptic 5-HT(1A) receptors in the specific anti-aggressive properties of 5-HT(1A) receptor agonists, the influence of the novel benzodioxopiperazine compound S-15535, which behaves in vivo as a competitive antagonist at postsynaptic 5-HT(1A) receptors and as an agonist at 5-HT(1A) autoreceptors, upon offensive and defensive aggression was investigated in wild-type rats using a resident-intruder paradigm. S-15535 exerted a potent dose-dependent decrease in offensive, but not defensive, aggressive behavior (inhibitory dose (ID)(50) = 1.11 mg/kg). This anti-aggressive profile was roughly similar to that of the potent pre- and postsynaptic 5-HT(1A) full agonist alnespirone (ID(50) = 1. 24). The drug's profound anti-aggressive actions were not accompanied by sedative side effects or signs of the "5-HT(1A) receptor-mediated behavioral syndrome," which are characteristically induced by prototypical 5-HT(1A) receptor agonists like 8-OH-DPAT and buspirone. The selective pre- and postsynaptic 5-HT(1A) antagonist WAY-100635, which was inactive given alone, abolished the anti-aggressive effects of S-15535 and alnespirone, thereby confirming the involvement of 5-HT(1A) receptors. Furthermore, combined administration of S-15535 and alnespirone elicited an additive anti-aggressive effect, providing further support for somatodendritic 5-HT(1A) receptor involvement. Finally, the postsynaptic 5-HT(1A) antagonistic properties of S-15535 were confirmed by showing blockade of the alnespirone-induced hypothermia, a postsynaptic 5-HT(1A) mediated response in the rat. These data provide extensive evidence that the anti-aggressive effects of 5-HT(1A) receptor agonists are expressed via their action on somatodendritic 5-HT(1A) autoreceptors, thereby most likely attenuating intruder-activated serotonergic neurotransmission.

Anxiolytic-like effects of selective mineralocorticoid and glucocorticoid antagonists on fear-enhanced behavior in the elevated plus-maze.

The effects of intracerebroventricular (ICV) administration of the mineralocorticoid receptor (MR) antagonist, RU28318, and the glucocorticoid receptor (GR) antagonist, RU38486, were studied on behavior of rats exposed to a compartment previously associated with a stressor, and placed subsequently in an elevated plus-maze test. Fear-motivated immobility behavior was attenuated by the MR antagonist in a dose of 50 or 100 ng ICV, whereas the GR antagonist alone or simultaneous administration of both antagonists had no significant effect. In the elevated plus-maze, immediately after the exposure to the conditioned stressor, both the GR antagonist (50 ng) and MR antagonist (50 ng) increased the percentage of time the rats spent on open arms, and increased the amount of entries into these open arms. These data are interpretated in terms of the involvement of the GR and MR in fear and anxiety.

Physiological and behavioral effects of chronic intracerebroventricular infusion of corticotropin-releasing factor in the rat.

The present study was conducted to investigate the long-term effects of chronic elevation of centrally circulating levels of corticotropin-releasing factor (CRF) on behavior and physiology. For this purpose ovine CRF was infused continuously for a period of 10 days into the lateral ventricle of rats with the aid of osmotic pumps (calculated CRF delivery was 4.9 micrograms/day). Changes in daily rhythms in body temperature and home cage motor activity were recorded telemetrically during the infusion period. The most prominent physiological findings were a delayed body weight gain and a long-lasting hyperthermia following CRF infusion. The peptide treatment furthermore increased adrenal weight and suppressed the weight of the thymus at the end of the experiment. Behaviorally, CRF administration elicited a short-lasting increase in activity during the light phase and an increased anxiety in an elevated plus-maze 1 week after the start of infusion. The similarities between the present results and the long-term changes previously described in behaviorally stressed rats indicate that chronically elevated levels of CRF in the brain might play an important role in the induction and persistence of stress-related behavioral and physiological disorders.

Behavioral and physiological consequences of repeated daily intracerebroventricular injection of corticotropin-releasing factor in the rat.

The present study was conducted to investigate the long-term consequences of repeated daily bolus injections of corticotropin-releasing factor (CRF) intracerebroventricularly (ICV) on ongoing locomotor activity and physiology in the home cage of individually housed rats. For this purpose ovine CRF (1 microgram/3 microliters) was injected once daily during the early resting phase into the lateral ventricle for a period of 10 days. Changes in daily rhythms in heart rate, body temperature and motor activity were recorded telemetrically before and during the treatment period. Daily central CRF injection delayed the body weight gain, increased adrenal weight, and decreased the weight of the thymus at the end of the experiment. The acute behavioral and physiological responses to CRF did not habituate with repetition of treatment. CRF treatment also failed to affect the long-term regulation of baseline heart rate, body temperature and motor activity during the light phase, as measured during the hour preceding the daily CRF injection. Mean heart rate during the dark phase was, however, significantly decreased in CRF-treated rats during the whole experimental 10-day period, without any sign of habituation. The failure of episodic CRF to affect long-term regulation of baseline body temperature during the light as well as the dark phase was noteworthy because an increased daytime body temperature lasting for several days is a characteristic marker of various behavioral stressors. Since a previous study showed that the temperature response during chronic CRF infusion was similar to the long-term effects of behavioral stress it is hypothesized that chronic but not episodic increases in central CRF levels are related to the induction and persistence of part of the stress-related behavioral and physiological disorders.

Housing familiar male wildtype rats together reduces the long-term adverse behavioural and physiological effects of social defeat.

Social stress in rats is known to induce long-lasting, adverse changes in behaviour and physiology, which seem to resemble certain human psychopathologies, such as depression and anxiety. The present experiment was designed to assess the influence of individual or group housing on the vulnerability of male Wildtype rats to long-term effects of inescapable social defeat. Group-housed rats were individually exposed to an aggressive, unfamiliar male conspecific, resulting in a social defeat. Defeated rats were then either individually housed or returned to their group. The changes in their behaviour and physiology were then studied for 3 weeks. Results showed that individually housed rats developed long-lasting, adverse behavioural and physiological changes after social defeat. Their body growth was significantly retarded (p < .05) between 7 and 14 days after defeat. When individually and group-housed rats were exposed to a mild stressor (sudden silence) 2 days after defeat, both groups became highly immobile. However, when exposure was repeated at day 21, individually housed rats were still highly immobile compared to group-housed rats which regained their normal mobility after only 7 days. In an open field test, also regularly repeated, individually housed rats took significantly longer to leave their home base and were also significantly less mobile than group-housed rats over the entire 3-week test period as well as at specific timepoints. When the rats were placed in an elevated plus-maze 14 days after defeat, those that were individually housed were significantly more anxious than those that were group-housed. When tested at 21 days after defeat in a combined dexamethasone (DEX)/corticotrophin-releasing factor (CRF) test, results showed that the hypothalamic-pituitary-adrenocortical (HPA) activity in individually housed rats was higher. This was evidenced in the latter animals by the fact that DEX was significantly less able to suppress the secretion of ACTH and corticosterone, and by a significantly higher release of ACTH after administration of CRF. Although the weights of the spleen and testes of the two groups did not differ, the adrenals of individually housed rats were larger and the thymus and seminal vesicles were smaller. We conclude that when rats are isolated after defeat, they show long-lasting, adverse behavioural and physiological changes that resemble symptoms of stress-related disorders. In contrast, when familiar rats are housed together these effects of a social defeat are greatly reduced. These findings show that housing conditions importantly influence the probability of long-term adverse behavioural and physiological effects of social defeat in male Wildtype rats.

Coping with stress in rats and mice: differential peptidergic modulation of the amygdala-lateral septum complex.

This chapter focuses on the parvicellular vasopressin (VP) system originating from the medial nucleus of the amygdala (MeA) and bed nucleus of the stria terminalis (BNST). The vasopressinergic fibers of these nuclei innervate a number of limbic brain areas including the septum-hippocampal complex. Interestingly, this VP system is sexually dimorphic and the VP synthesis in this system depends on circulating gonadal steroids. Studies in rats and mice show that the variation in the lateral septal VP network within the male gender is as large as the variation between the sexes as reported in the literature. Non-aggressive males are characterized by a far more extensive VP network and a higher VP content in the lateral septal area than aggressive males. A review of the literature on the function of lateral septal VP in the organization of behavior reveals not only a modulatory role of behavior in a social context, but also of fear- and anxiety-related behaviors. It is argued that these seemingly diverse functions might be explained by the concept of coping style. Extensive behavioral and physiological analyses in a variety of animal species show that males may be characterized by the way in which they cope with environmental challenges in general. Aggressive males tend to cope actively with their environment whereas non-aggressive males seem to accept the situation as it is more easily. In several tests, we determined the effects of chronic infusion of the V1 receptor antagonist locally into the lateral septal area in male rats. The main conclusion from these experiments is that LS VP does not modulate coping style in general. However, the experiments confirm the idea that LS VP has a certain degree of functional specificity in social behavior and social learning tasks. Together with the observation that the size and distribution of the vasopressinergic system may be highly variable between individual males in relation to their coping style, this suggests that the lateral septal vasopressinergic system is involved in the differential capacity of individuals to cope behaviorally with challenges of a social nature.

Long-lasting deficient dexamethasone suppression of hypothalamic-pituitary-adrenocortical activation following peripheral CRF challenge in socially defeated rats.

The present study focuses on the long-term changes in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis following two short-lasting episodes of intensive stress in the rat stress model of social defeat and the possible similarities with HPA functioning in human affective disorders. Male Wistar rats experienced social defeats on 2 consecutive days by an aggressive male conspecific. The long-term effect of these defeats on resting and ovine corticotropin-releasing factor (oCRF; intravenous (i.v.) 0. 5 microg/kg) induced levels of plasma ACTH and corticosterone (CORT) were measured 1 and 3 weeks later. In a second experiment the glucocorticoid feedback regulation of HPA function was tested in a combined dexamethasone (DEX)/CRF test (DEX; 25 microg/kg s.c., 90 min before oCRF injection, 0.5 microg/kg). The oCRF challenges were performed between 11.00 and 13.00 h (about three hours after start of the light phase). One week after defeat the ACTH response to CRF was significantly enhanced in defeated rats as compared to controls. Three weeks after defeat the ACTH response was back to control levels. The increased ACTH response 1 week after the stressor was not reflected in higher CORT levels. Neither were baseline ACTH and CORT levels affected by the prior stress exposure. DEX pretreatment inhibited pituitary adrenocortical activity, reflected both in reduced baseline and response values of ACTH and CORT. The ACTH response to CRF following DEX administration was significantly higher in defeated rats as compared to controls both at one and three weeks after defeat. A reduced DEX suppression of baseline secretion of ACTH appeared 3 weeks after defeat. The same tendency was apparent in response and baseline values of CORT. The differences in CORT between socially stressed and control treated rats, however, did not reach significance. The possible role of changes in glucocorticoid-(GR) and mineralocorticoid receptor (MR) binding in the altered regulation of HPA activity following defeat were studied in brain and pituitary of male Wistar rats 1 and 3 weeks after defeat. One week after defeat GR-binding decreased in hippocampus and hypothalamus. No changes were observed in GR-binding in the pituitary nor in MR-binding in any of the regions analysed. Three weeks after defeat GR-binding recovered in hippocampus and hypothalamus but at this time MR-binding in hippocampal tissue was seriously decreased. In a fourth experiment vasopressin (AVP) and CRF stores in the external zone of the median eminence (ZEME) were measured by quantitative immunocytochemistry one and three weeks after defeat and compared with controls. Social defeat failed to induce a change in the immunocytochemical stores of AVP or CRF. The present findings show that in rats short-lasting stressors like defeat induce long-lasting, temporal dynamic changes in the regulation of the HPA axis. Since these changes in time are reflected in GRs and MRs in different brain areas an altered corticosteroid receptor binding might play an important role in the affected HPA activity following defeat.

Long-lasting consequences of a social conflict in rats: behavior during the interaction predicts subsequent changes in daily rhythms of heart rate, temperature, and activity.

This study shows that the long-term consequences of a social conflict in rats do not depend on the physical intensity of the fight in terms of aggression received but, especially, on how the subjects deal with it. Experimental rats were introduced into the cage of an aggressive conspecific for 1 hr, and the effects on daily rhythms of heart rate, body temperature, and activity thereafter were measured by means of telemetry. In some rats, the confrontation caused a strong decrease in the daily rhythm amplitude that lasted up to 3 weeks, whereas other subjects showed only minor changes. The changes in rhythm amplitude did not correlate with the number of attacks received from the territory owner. Contrary to this, the changes showed a clear negative correlation with the aggression of the experimental rats themselves. Subjects fighting back and counterattacking the cage owner subsequently had a smaller reduction in rhythm amplitude.

Fear-potentiation in the elevated plus-maze test depends on stressor controllability and fear conditioning.

The purpose of the study was to determine which stressor qualities (escapable vs. inescapable stress and unconditioned vs. conditioned stress) can potentiate fear in the elevated plus-maze. While inescapable stress potentiated fear, escapable stress did not, but escapable stress increased the locomotor activity (closed arm entries). Inescapable stress only potentiated fear when re-exposure to the former shock compartment, 24 h after footshock and without further footshock, took place just before to 90 min before testing in the elevated plus-maze. We conclude that fear-potentiation in the plus-maze depends on stressor controllability and contextual conditioning. Fear-potentiation was reduced by the anxiolytic diazepam (0.5, 1.0 and 2.0 mg/kg, s.c.) and was further enhanced by the anxiogenic DMCM (1.0 mg/kg, s.c). The fear-potentiated plus-maze test may be a valuable tool in the search for novel anxiolytics and in the study of the neurobiology of fear-potentiation, fear conditioning and generalization of fear.

Brain benzodiazepine receptor-mediated effects on plasma catecholamine and corticosterone concentrations in rats.

The effects of the benzodiazepine (BDZ) receptor agonist chlordiazepoxide (CDP) and antagonist flumazenil (Ro 15-1788), given alone and in combination, on basal and novel environment stress (NES)-elevated plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) contents were investigated. When administered on their own, a medium dose of CDP (2.5 mg/kg) and a moderate dose of flumazenil (5 mg/kg) did not affect basal hormone levels. However, flumazenil potentiated the NES-induced CS elevation and suppressed the NA rise in response to NES. The 2.5 mg/kg dose of CDP attenuated the NES-elicited rise of CS and A, without changing the NES-enhanced NA concentrations. High doses of CDP (10 and 12.5 mg/kg), which elevated basal CS levels, prevented a further CS increase by NES and completely abolished the NA and A response to NES. The CDP effects on CS and NA were antagonized by pretreatment with flumazenil, in contrast to the CDP effect on A which was not blocked. The data indicate that brain (central-type) BDZ receptor systems are involved in regulating the neurosympathetic and adrenocortical, but not adrenomedullary, responses to mild stress.

Changes in plasma corticosterone and catecholamine contents induced by low doses of deltamethrin in rats.

The effects of low doses of (S)-alpha-cyano-3-phenoxybenzyl (1R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate (Roussel UCLAF, Paris, France), (deltamethrin) upon sympathetic-adrenomedullary and pituitary-adrenocortical activity were investigated in rats by measuring plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) concentrations. Blood was sampled from freely-moving animals provided with heart catheters at short intervals up to 60 min after intravenous administration of deltamethrin (0.05, 0.15 and 0.45 mg/kg) or vehicle. Behavioral activity was recorded shortly after the sampling times. Time course and magnitude of the biochemical changes were compared with the effects of exposure to uncontrollable white noise in a similar sampling and recording procedure. Dose-dependent increases were observed for NA and A as well as for CS contents. The dose-response relations however, were different among the neuro-edocrine respondents. Discrete step-wise increases were observed for plasma CS only, indicating greater sensitivity for neurotoxical actions. Already at a dose of 0.15 mg/kg of deltamethrin, CS contents rose to values that were considerably higher than those found during noise exposure. In contrast, plasma CA concentrations increased to noise stress values only after the 0.45 mg/kg dose. The behavioral activity pattern appeared to resemble both CA patterns. The results suggest that rather low doses of deltamethrin elicit vigorous autonomic and neuro-endocrine responses that indicate high levels of stress, presumably caused by the neurotoxic effect of the insecticide.

A role for the autonomic nervous system in modulating the immune response during mild emotional stimuli.

The role of the autonomic nervous system in the modulation of the immune response to emotional stimuli, was established in rats subjected to the passive avoidance test. An increase in splenic primary antibody response directed against SRBC was found after exposure of rats to the passive avoidance apparatus (novelty). Both local surgical denervation of the spleen and beta-receptor blockade (timolol, 1 mg/kg i.p. 1 h prior to testing) prevented the increase in primary antibody response.