Ovariectomy-induced depressive-like behavior and brain glucose metabolism changes in female rats are not affected by chronic mild stress.

The increased incidence of depression in women going through peri-menopause suggests that fluctuations in estrogen levels may increase the risk of developing depression. Nonetheless, this psychiatric disorder is likely to be multifactorial and consequently an additional trigger may be needed to induce depression in this population. Stress could be such a trigger. We therefore investigated the effect of ovarian estrogen depletion and chronic mild stress (CMS) on depressive-like behavior and brain metabolism in female rats. Approximately 2 and 9 weeks after estrogen depletion by ovariectomy, behavioral changes were assessed in the open-field test and the forced swim test, and brain metabolism was measured with [18F]FDG PET imaging. A subset of animals was subjected to a 6-weeks CMS protocol starting 17 days after ovariectomy. Short-term estrogen depletion had a significant effect on brain metabolism in subcortical areas, but not on behavior. Differences in depressive-like behavior were only found after prolonged estrogen depletion, leading to an increased immobility time in the forced swim test. Prolonged estrogen depletion also resulted in an increase in glucose metabolism in frontal cortical areas and hippocampus, whereas a decrease glucose metabolism was found in temporal cortical areas, hypothalamus and brainstem. Neither short-term nor prolonged estrogen depletion caused anxiety-like behavior. Changes in body weight, behavior and brain glucose metabolism were not significantly affected by CMS. In conclusion, ovarian estrogen depletion resulted in changes in brain metabolism and depressive-like behavior, but these changes were not enhanced by CMS.

Repeated social stress leads to contrasting patterns of structural plasticity in the amygdala and hippocampus.

Previous studies have demonstrated that repeated immobilization and restraint stress cause contrasting patterns of dendritic reorganization as well as alterations in spine density in amygdalar and hippocampal neurons. Whether social and ethologically relevant stressors can induce similar patterns of morphological plasticity remains largely unexplored. Hence, we assessed the effects of repeated social defeat stress on neuronal morphology in basolateral amygdala (BLA), hippocampal CA1 and infralimbic medial prefrontal cortex (mPFC). Male Wistar rats experienced social defeat stress on 5 consecutive days during confrontation in the resident-intruder paradigm with larger and aggressive Wild-type Groningen rats. This resulted in clear social avoidance behavior one day after the last confrontation. To assess the morphological consequences of repeated social defeat, 2 weeks after the last defeat, animals were sacrificed and brains were stained using a Golgi-Cox procedure. Morphometric analyses revealed that, compared to controls, defeated Wistar rats showed apical dendritic decrease in spine density on CA1 but not BLA. Sholl analysis demonstrated a significant dendritic atrophy of CA1 basal dendrites in defeated animals. In contrast, basal dendrites of BLA pyramidal neurons exhibited enhanced dendritic arborization in defeated animals. Social stress failed to induce lasting structural changes in mPFC neurons. Our findings demonstrate for the first time that social defeat stress elicits divergent patterns of structural plasticity in the hippocampus versus amygdala, similar to what has previously been reported with repeated physical stressors. Therefore, brain region specific variations may be a universal feature of stress-induced plasticity that is shared by both physical and social stressors.

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.

Adolescent social stress does not necessarily lead to a compromised adaptive capacity during adulthood: a study on the consequences of social stress in rats.

Childhood bullying or social stress in adolescent humans is generally considered to increase the risk of developing behavioral disorders like depression in adulthood. Juveniles are hypothesized to be particularly sensitive to stressors in their environment due to the relatively late maturation of brain areas that are targeted by stress such as the prefrontal cortex and hippocampus. In our study male adolescent rats were subjected to repeated social defeat on postnatal day (PND) 28, 31 and 34 (experiment 1) or to daily social defeats between PND 35 and 42 (experiment 2). Adolescent rats in experiment 1 were socially housed in pairs with a male of similar age during and after the social defeat. In experiment 2 adolescents were housed either alone or with an age-mate for 7 days (PND 35-42) next to either a highly aggressive or a non-aggressive adult male neighbor with whom a repeated physical interaction was allowed. In experiment 1 the adolescent defeats affected subsequent play behavior with the cage mate. Socially stressed rats more frequently initiated play behavior but also adopted more frequently submissive postures during the play fights. As adults, they seemed to cope behaviorally and physiologically better with a similar exposure to a residential aggressive male rat than unstressed controls. In experiment 2 acute effects of adolescent social stress were studied on neuroplasticity markers like hippocampal cell proliferation and neurogenesis as well as hippocampal brain-derived neurotrophic factor (BDNF) levels. The 2nd experiment also studied long-term effects of the adolescent stress in the response to an adult social defeat. A few acute but minor changes in brain plasticity markers and behavior were observed but these were transient and no behavioral or physiological effects persisted into adulthood. The results from both experiments support the theory developed in the so-called "match-mismatch hypothesis" which claims that the final consequence of childhood adversity depends on how well the early life environment matches the challenges in later life. Socially stressed adolescents are rather resilient to the lasting behavioral and physiological effects of the stress exposure if they are socially housed afterward and have the ability to recover.

Stress revisited: a critical evaluation of the stress concept.

With the steadily increasing number of publications in the field of stress research it has become evident that the conventional usage of the stress concept bears considerable problems. The use of the term 'stress' to conditions ranging from even the mildest challenging stimulation to severely aversive conditions, is in our view inappropriate. Review of the literature reveals that the physiological 'stress' response to appetitive, rewarding stimuli that are often not considered to be stressors can be as large as the response to negative stimuli. Analysis of the physiological response during exercise supports the view that the magnitude of the neuroendocrine response reflects the metabolic and physiological demands required for behavioural activity. We propose that the term 'stress' should be restricted to conditions where an environmental demand exceeds the natural regulatory capacity of an organism, in particular situations that include unpredictability and uncontrollability. Physiologically, stress seems to be characterized by either the absence of an anticipatory response (unpredictable) or a reduced recovery (uncontrollable) of the neuroendocrine reaction. The consequences of this restricted definition for stress research and the interpretation of results in terms of the adaptive and/or maladaptive nature of the response are discussed.

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.

Differential effects of stress on adult hippocampal cell proliferation in low and high aggressive mice.

Male wild house mice selected for a long (LAL) or a short (SAL) latency to attack a male intruder generally show opposing behavioural coping responses to environmental challenges. LAL mice, unlike SAL mice, adapt to novel challenges with a highly reactive hypothalamic-pituitary-adrenal axis and show an enhanced expression of markers for hippocampal plasticity. The present study aimed to test the hypothesis that these features of the more reactive LAL mice are reflected in parameters of hippocampal cell proliferation. The data show that basal cell proliferation in the subgranular zone (SGZ) of the dentate gyrus, assessed by the endogenous proliferation marker Ki-67, is lower in LAL than in SAL mice. Furthermore, application of bromodeoxyuridine (BrdU) over 3 days showed an almost two-fold lower cell proliferation rate in the SGZ in LAL versus SAL mice. Exposure to forced swimming resulted, 24 h later, in a significant reduction in BrdU + cell numbers in LAL mice, whereas cell proliferation was unaffected by this stressor in SAL mice. Plasma corticosterone and dentate gyrus glucocorticoid receptor levels were higher in LAL than in SAL mice. However, no differences between the SAL and LAL lines were found for hippocampal NMDA receptor binding. In conclusion, the data suggest a relationship between coping responses and hippocampal cell proliferation, in which corticosterone may be one of the determinants of line differences in cell proliferation responses to environmental challenges.

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-HT(1A)) receptors, both in receptor binding and in mRNA levels, in the aggressive line [Brain Res 736 (1996) 338]. The aim of this experiment was to study whether similar differences in 5-HT(1A) 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-HT(1A) 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-HT(1A) 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-HT(1A) 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.

Behavioral and physiological responses to stress are affected by high-fat feeding in male rats.

Interactions between monoaminergic neurochemistry and macronutrient intake have been frequently shown. Because monoaminergic systems in the brain are also closely involved in behavioral and physiological stress responses it can be hypothesized that differences in the macronutrient composition of diets are reflected in these responses. The present studies, therefore, were designed to assess the consequences of a change in dietary macronutrient composition on a variety of physiological and behavioral responses (both acute and long-term) to a number of stressors. The effect of chronic high-fat (HF; 61% kcal from fat) feeding on the stress responses was compared with controls receiving regular high-carbohydrate (HC; 63% kcal from carbohydrates) laboratory chow. Rats were kept on this diet for at least 2 months before they were exposed to either psychological (social defeat) or physiological (lipopolysaccharide, LPS, administration) stress. At baseline, chronic HF feeding caused a slight, but significantly reduction in body temperature relative to that observed in HC-fed rats. Following social defeat or LPS injection, HF feeding caused a faster recovery of the body temperature increase relative to animals on the HC diet. Stress-induced suppression of home cage locomotor activity and body weight gain were also reduced by HF feeding. The serotonergic 5-HT(1a) receptor hyposensitivity that was observed in HC-fed rats 2 weeks after stress was absent in the HF regimen. Although the present results cannot be readily interpreted as showing purely beneficial effects of high-fat diets on stress responsivity, the findings in the present study do encourage further investigation of possible ameliorating effects of high-fat diets on aspects of the behavioral and physiological response stress.

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.

Social stress, autonomic neural activation, and cardiac activity in rats.

Animal models of social stress represent a useful experimental tool to investigate the relationship between psychological stress, autonomic neural activity and cardiovascular disease. This paper summarizes the results obtained in a series of experiments performed on rats and aimed at verifying whether social challenges produce specific modifications in the autonomic neural control of heart rate and whether these changes can be detrimental for cardiac electrical stability. Short-term electrocardiographic recordings were performed via radiotelemetry and the autonomic input to the heart evaluated by means of time-domain heart rate variability measures. Compared to other stress contexts, a social defeat experience produces a strong shift of autonomic balance toward sympathetic dominance, poorly antagonized by vagal rebound, and associated with the occurrence of cardiac tachyarrhythmias. These effects were particularly severe when a wild-type strain of rats was studied. The data also suggest that the cardiac autonomic responses produced by different types of social contexts (dominant-subordinate interaction, dominant-dominant confrontation, social defeat) are related to different degrees of emotional activation, which in turn are likely modulated by the social rank of the experimental animal and the opponent, the prior experience with the stressor, and the level of controllability over the stimulus.

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.

Corticosterone modifies muscarinic receptor immunoreactivity in rat hippocampus.

In the present study we report the effect of corticosterone in the regulation of hippocampal muscarinic acetylcholine receptor immunoreactivity (mAChR-ir) expression in rats. Adrenalectomy (ADX) or a single injection of a mineralocorticoid antagonist RU-28318 (1.0 mg/100 g body weight (b.w.)) in adrenally intact rats 24 h prior to sacrifice revealed an increased mAChR-ir in hippocampal CA1 and CA3 areas. Corticosterone replacement (100 microg/100 g b.w.) prevented the increase in mAChR-ir of ADX animals. However, glucocorticoid receptor antagonist (RU38486) treatment in adrenally intact rats failed to affect the mAChR immunolabeling. These results point to a modulation of muscarinic receptors by corticosterone that is predominantly mediated by the mineralocorticoid receptor.

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.

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.

Vulnerability to arrhythmias during social stress in rats with different sympathovagal balance.

An increased activity of the sympathetic nervous system is an important factor in the genesis of ventricular arrhythmias. Changes in average R-R interval, R-R interval variability (indirect measure of sympathovagal balance), occurrence of arrhythmias, and plasma norepinephrine concentrations were measured during a social stress episode (defeat) in two strains of rats, Wistar and wild type, which were supposed to differ in their autonomic stress responsiveness. Electrocardiograms were telemetrically recorded, and blood samples were withdrawn through jugular vein catheters from healthy, freely moving animals. R-R interval variability was estimated by the following time-domain parameters: the standard deviation of the mean R-R interval, the coefficient of variance, and the root mean square of successive differences in R-R interval. Average R-R interval and R-R interval variability measures, as well as plasma norepinephrine concentrations, indicated a higher sympathetic tone, a larger sympathetic responsiveness, and a lower parasympathetic antagonism after sympathetic activation in wild-type animals, which also showed a much higher incidence of arrhythmias (ventricular premature beats), compared with Wistar rats. These two strains might represent a valuable experimental model for studying the mechanisms (cellular/electrophysiological) responsible for the susceptibility to arrhythmias in healthy individuals exposed to stressful situations.

Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning.

Corticosteroids from the adrenal cortex influence a variety of behaviours including cognition, learning and memory. These hormones act via two intracellular receptors, the mineralo-corticoid receptor (MR) and the glucocorticoid receptor (GR). These two receptor types display a high concentration and distinct distribution in the hippocampus, a brain region which is directly involved in the regulation of spatial orientation and learning. In this study, repeated subcutaneous administration of the mineralocorticoid receptor antagonist RU28318 (1.0 mg/100 g body weight), the glucocorticoid receptor blocker RU38486 (2.5 mg/100 g body weight), or a combination of both antagonists were investigated for their effects on working--and reference memory in morning and afternoon trials during 8 subsequent days in food rewarded spatial learning in a hole board task. Each rat received one dose of either vehicle (2% ethanol in PEG 400), RU28318, RU38486 or the combination of both antagonists directly after the first trial on training days 1, 3, 5, and 7. The experiments demonstrated that repeated blockade of mineralocorticoid receptors impairs reference memory reflected in the morning--as well as in the afternoon trial, whereas blockade of glucocorticoid receptors has little effect on this type of cognitive behaviour. Furthermore, combined blockade of MRs and GRs resulted in a decrease, in both daily trials, in reference memory as well as working memory performance. These findings suggest that in this spatial learning paradigm, the impairment of working memory required blockade of both receptor types, while reference memory performance involves predominantly the mineralocorticoid receptors.

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.

Enhanced 5-HT1A receptor expression in forebrain regions of aggressive house mice.

The brain 5-HT1A receptor system in male wild house mice selected for high and low offensive aggression was investigated by autoradiographic analysis of in situ hybridization and radioligand binding. In high-aggressive mice, characterized by a short attack latency, the rise in plasma corticosterone concentration during the early dark phase was reduced. At that time the level of 5-HT1A mRNA in the dorsal hippocampus (dentate gyrus and CA1) was twice the amount measured in low-aggressive mice that had long attack latency and high plasma corticosterone level. Increased postsynaptic 5-HT1A receptor radioligand binding was found in dentate gyrus, CA1, lateral septum, and frontal cortex. No difference in ligand binding was found for the 5-HT1A autoreceptor on cell bodies in the dorsal raphe nucleus. In conclusion, genetic selection for high offensive aggression co-selects for reduced (circadian peak) level in plasma corticosterone and increased postsynaptic 5-HT1A receptor number in limbic and cortical regions.

Adrenaline release by the 5-HT1A receptor agonist 8-OH-DPAT is partly responsible for pituitary activation.

In male Wistar rats the effect of adrenalectomy on pituitary activation by the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), was studied. Rats were injected intravenously with 8-OH-DPAT (0.10 mg/kg) in their home cages. Blood samples were withdrawn from freely moving cannulated rats for determination of plasma adrenaline and plasma adrenocorticotropin hormone (ACTH). Adrenalectomized rats showed almost no measurable amounts of plasma adrenaline, but these animals had elevated baseline plasma (ACTH levels as compared to sham-operated rats. 8-OH-DPAT treatment led to a large plasma adrenaline response in the sham-operated animals, which was abolished after adrenalectomy. The plasma ACTH response to 8-OH-DPAT was significantly diminished in the adrenalectomized rats as compared to sham animals. This blunted ACTH response in adrenalectomized rats, however, was still considerable in magnitude. The present data thus indicate that the plasma ACTH response to 8-OH-DPAT is due to at least two different mechanisms. First, via 5-HT1A receptor-mediated adrenaline release, which may consequently stimulate the pituitary. Second, a direct action of 8-OH-DPAT on hypothalamic 5HT1A receptors is assumed, independent of peripheral adrenaline release.