Spatial learning in pigs: effects of environmental enrichment and individual characteristics on behaviour and performance.

This study investigated the effects of both environmental enrichment and individual behavioural characteristics on spatial cognitive capabilities of pigs, using a novel latent spatial learning paradigm based on Tolman's detour experiments (1948). Pigs were housed either in 'barren' pens or in pens enriched with straw bedding from birth. Pigs were restrained in a Backtest at 10 and 17 days postpartum. Based on their escape behaviour in this test, which has been shown to reflect their behavioural style, six 'high-resisting'(HR) and six 'low-resisting' (LR) pigs were selected from each housing environment (n = 24 in total). At 12 weeks of age, pairs of pen mates (LR and HR) were exposed to a maze three times (exploration trials). Pigs were then placed individually in the maze, and social reinstatement proved to be a strong incentive to find the exit leading to the home pen. We subsequently blocked the direct route to the exit, forcing animals to find a detour (memory test 1, MT1). This test was repeated once to investigate the relative improvement, i.e. detour learning (memory test 2, MT2). Housing condition and Backtest response strongly affected exploration patterns. In spite of this, no effects on performance during the subsequent memory tests were found. Performance was substantially improved in MT2, indicating that once a goal is apparent, pigs are able to solve a complex spatial memory task easily. In conclusion, social reinstatement provided a good incentive to complete a spatial task, and the substantial improvement in performance between MT1 and MT2 stresses the need for task complexity when testing spatial memory in pigs. Housing conditions or individual behavioural style did not affect spatial memory during MT1 or MT2. However, housing environment and behavioural style strongly affected explorative behaviour of pigs in an unfamiliar maze during both exploration trials and memory tests. This implicates that apparent effects of environmental enrichment on spatial learning and memory in pigs might reflect differences in explorative patterns rather than in cognitive processes.

Altered neuropeptide Y and neurokinin messenger RNA expression and receptor binding in stress-sensitised rats.

A single session of footshocks in rats causes long-lasting sensitisation of behavioural, hormonal and autonomic responses to subsequent novel stressful challenges as well as altered pain sensitivity. These changes mimic aspects of post-traumatic stress disorder in humans. Our aim was to identify neuropeptide substrates in the central nervous system involved in stress sensitisation. Male Wistar rats were exposed to ten footshocks in 15 min (preshocked) or placed in the same cage without shocks (control). Two weeks later, rats were placed in a novel cage, subjected to 5 min of 85 dB noise, and returned to their home cage. Rats were killed either before or 1 h after noise and their brains processed for in situ hybridization for neuropeptide Y (NPY) and beta-preprotachykinin-I (PPT) mRNA. Additional groups of rats were killed under basal conditions and brains processed for NPY and neurokinin receptor binding with radiolabelled ligands. Two weeks after footshock treatment NPY mRNA expression was increased in the basolateral amygdala and showed preshockxnoise interaction in the locus coeruleus (down after noise in controls, lower basal and unchanged after noise in preshocked). PPT expression in the lateral parabrachial nucleus also showed preshockxnoise interaction (up after noise in controls, higher basal and down after noise in preshocked), and was increased after noise in the periaquaeductal grey. NK1 receptor binding in the agranular insular cortex and arcuate nucleus of the hypothalamus and NK2 receptor binding in the amygdala was lower in preshocked rats than in controls. Altered expression of NPY in the basolateral amygdala and locus coeruleus could contribute to or compensate for behavioural and autonomic sensitisation in preshocked rats. Altered PPT expression in the parabrachial nucleus may be involved in the altered pain processing seen in this model. Lower NK1 and NK2 receptor numbers in cortex, hypothalamus and amygdala may reflect secondary adaptations to altered neuropeptide release. These long-term changes in brain neuropeptide systems could offer novel leads for pharmacological modulation of long-term stress-induced sensitisation.

Involvement of group II metabotropic glutamate receptors in stress-induced behavioural sensitization.

RATIONALE: A short session of repeated foot shocks in rats causes long-lasting sensitization of behavioural, hormonal and autonomic responses to novel stressful challenges. The behavioural sensitization can be reduced by anxiolytics and mimics aspects of stress-induced changes in patients with post-traumatic stress disorder. OBJECTIVES: The aim of this study was to test the efficacy of a group II metabotropic glutamate receptor (mGluR) agonist and assess altered brain mGluR receptor expression in shock-sensitized rats. MATERIALS AND METHODS: Male Wistar rats were exposed to a 15-min session with ten 6-s foot shocks (preshocked). One and 2 weeks later, rats were intraperitoneally injected with the group II metabotropic glutamate receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) or vehicle, and 30 min later exposed to 5 min of 85 dB noise. For in situ hybridization with probes for mGluR1, mGluR2, mGluR3 and mGluR5, preshocked and control rats were killed under basal conditions 2 weeks after foot shocks and their brains cryosectioned. RESULTS: APDC had no clear effect in controls, but dose-dependently reduced high immobility and increased low locomotion and rearing seen in preshocked rats to the levels of controls. mGluR3 expression was increased in the basolateral nucleus of the amygdala, and mGluR2 expression was increased in the agranular insular cortex of preshocked rats compared to controls. CONCLUSIONS: Shock-induced behavioural sensitization in rats is reduced by acute treatment with a group II metabotropic glutamate receptor agonist. This effect may depend on the increased expression of amygdala mGluR3, which could be hypothesized as an endogenous mechanism to counteract stress-induced neuronal sensitization.

Duodenal pain and spinal morphine induce conditioned taste aversion in rats.

Conditioned taste aversion (CTA) is a behavioural response essential to the survival of an individual. The combination of taste and odour of most foods provides a strong conditioned stimulus (CS) for an animal to respond in an appropriate way to any harmful unconditioned stimuli (US) that follow. The most widely used conditioned stimuli are drinkable sweet solutions, such as saccharin and sucrose. CTA-like responses are also found for environmental unconditioned stimuli, but these usually take longer training. In the present study, the aversive nature of a duodenal distention with an implanted balloon catheter was studied in freely moving rats using either CTA against a sucrose solution, or a light-dark passive avoidance (PA) paradigm. In addition, the effect of spinal morphine on CTA and the cardiovascular response to duodenal distention were studied. CTA could be induced by a single, but long-lasting 20-minute duodenal distention, which did not induce PA behaviour in a light-dark box. Spinal infusion of morphine alone induced CTA, suggesting that the model is unsuitable to investigate spinal pharmacological modulation of visceral pain. Spinal morphine did reduce the cardiovascular response to duodenal distention, strengthening its validity as a visceral pain model. Since CTA is a complicating factor in the field of chemotherapy in cancer patients and spinal morphine causes nausea and vomiting in humans, CTA may also complicate spinal drug treatment or anaesthesia.

Individual reactivity to the open-field predicts the expression of cardiovascular and behavioural sensitisation to novel stress.

Posttraumatic stress disorder (PTSD) is the fourth most common psychiatric disorder. It is associated with cardiovascular disorders and irritable bowel syndrome (IBS). Besides stressful life-events, a prior history of gastrointestinal infection is a predisposing factor for the development of IBS. Only a proportion of persons exposed to traumatic events develop PTSD. Several factors, like genetic predisposition, stressor intensity, cognitive appraisal mechanisms and coping processes influence the likelihood of developing PTSD after exposure to a trauma. We used a single session of footshocks in rats, an animal model with a high degree of validity for PTSD, to study whether transient colonic inflammation alters local and distal visceral sensitivity, and whether reactivity to the open-field (low (LA) or high (HA) active) predicts long-term stress-induced behavioural and cardiovascular sensitisation and altered visceral pain sensitivity. A distention series and noise challenge were given 2 weeks after foot-shocks, followed by a transient colonic inflammation period and a second distention series and noise challenge 4 weeks after foot-shocks. During exposure to noise, both before and after inflammation, footshocked rats showed increased immobility compared to controls, which was significantly greater in LA rats than in HA rats. LA preshocked rats also showed a greater blood pressure response to the noise test, but this only became evident in the second noise-test. Neither footshocks nor colonic inflammation affected duodenal pain sensitivity. The results provide additional evidence for long-lasting cardiovascular hyperresponsivity after a stressful event and indicate that its degree is predicted by personality traits or coping style.

Individual reactivity to the open-field predicts the expression of stress-induced behavioural and somatic pain sensitisation.

Posttraumatic stress disorder (PTSD) is the fourth most common psychiatric disorder. It is associated with somatic complaints like pain problems. Only a proportion of persons exposed to traumatic events develop PTSD. Several factors, like genetic predisposition, stressor intensity, cognitive appraisal mechanisms and coping processes influence the likelihood of developing PTSD after exposure to a trauma. We used a single session of footshocks in rats, an animal model with a high degree of validity for PTSD, to study whether individual behavioural traits predict long-term stress-induced sensitisation of behavioural responsivity and somatic pain sensitivity and therefore can act as a vulnerability factor. Rats were selected for low (LA) and high (HA) open-field locomotor reactivity and then underwent a single session of footshocks. Two to 5 weeks after footshocks, behavioural sensitisation was investigated using a noise challenge, an electrified prod challenge and a forced swim test. Somatic pain sensitivity was measured using a tail-immersion test. During exposure to noise in a novel cage, footshocked rats showed increased immobility compared to controls, which was significantly greater in LA than in HA rats. Footshocked rats showed increased burying in the electrified prod challenge and no effect was found in the forced swim test. Footshocks caused hyperalgesia in LA rats, but hypoalgesia in HA rats. We conclude that low open-field locomotor reactivity predicts the degree of stress-induced behavioural sensitisation and the direction of altered somatic pain sensitivity, suggesting that an anxiety-prone personality or passive coping style may increase the risk of developing stress-related psychosomatic disorders.

Autonomic and neuroendocrine responses to a psychosocial stressor in adults with autistic spectrum disorder.

Objective of the study was to replicate in adults our previous findings of decreased heart rate and normal endocrine responses to stress in autistic children and to elucidate the discrepancy between autonomic and endocrine stress responses by including epinephrine, norepinephrine, oxytocin and vasopressin measurements. Ten autistic spectrum disorder (ASD) adults were compared to 14 healthy controls in their response to a psychosocial stressor (public speaking). ASD patients showed decreased heart rate, but normal cortisol responses, consistent with our prior findings in children. No differences in norepinephrine, epinephrine, oxytocin or vasopressin responses to stress were found. However, in contrast to previous findings in low functioning autistic children, ASD adults showed increased basal oxytocin levels, which may be related to developmental factors.

Depression with above-normal plasma vasopressin: validation by relations with family history of depression and mixed anxiety and retardation.

An anxious-retarded subtype of depression has been derived from the DSM-IV category of melancholia. It is defined by combined high scores for anxiety and retardation, and is related to family history of depression and increased plasma vasopressin (AVP) levels. Central problems concerning this hypothesized subcategory are whether elevated plasma AVP is related to family history, whether it would be better operationalized by a cut-off level for plasma AVP than as continuous variable, and whether the anxious-retarded phenotype would be better described in terms that account for full variability of mixed anxiety and retardation. A previous study suggested that above-normal plasma AVP was a more useful endophenotypic parameter than plasma AVP as a continuous variable. To answer these and related questions, 81 patients were investigated. Receiver Operating Characteristic analyses yielded a cut-off value of 5.56 pg/ml for above-normal plasma AVP, log-transformed plasma AVP (ln (AVP)) was used as continuous variable, and the correlation between anxiety and retardation was used to account for full variability of the anxious-retarded phenotype. Family history was related to above-normal plasma AVP (n = 16) and non-significantly to ln (AVP). Depression with above-normal plasma AVP, as well as familial depression with above-normal plasma AVP, showed a high correlation between anxiety and retardation, and this correlation was significantly higher than that found in the depressed patient control groups. The data support the delimitation of a largely familial depression with above-normal plasma AVP, vasopressinergic activation of the hypothalamus-pituitary-adrenal axis and a variable anxious-retarded phenotype.

Lower birth weight and attenuated adrenocortical response to ACTH in offspring from sows that orally received cortisol during gestation.

Prenatal stress is known to affect several offspring characteristics, but its effects depend among other factors on the period of gestation in which it is applied. In the present study, oral administration of hydrocortisone-acetate (HCA) was used to elevate cortisol concentrations in pregnant sows to levels also observed after psychological stress. HCA was administered during three different periods of gestation (115 days in pigs): period 1: 21-50 (P1, n = 10), period 2: 51-80 (P2, n = 10) and period 3: 81-110 (P3, n = 10) days after insemination. Control sows (n = 11) received vehicle from 21-110 days after insemination. When P1-, P2- and P3-sows did not receive HCA, they also received vehicle. During gestation, weekly saliva samples were taken from the sows to determine salivary cortisol concentrations. Treatment effects on sow, litter and piglet characteristics were determined. In addition, two female piglets per litter were subjected to an ACTH-challenge test at 6 weeks of age to determine the adrenocortical response to ACTH. Pigs were slaughtered at 6 months of age and slaughter weight, back fat thickness and percentage of lean meat were analysed. During the period of treatment with HCA, salivary cortisol concentrations were increased in P1-, P2- and P3-sows compared to control sows (P < 0.01). The total number of piglets born per litter did not differ among treatment groups (P > 0.30), but pooled HCA-litters had a higher percentage of live born piglets (P < 0.05) and fewer mummies than control litters (P < 0.05). Gestation length did not differ among treatment groups (P = 0.21), but did affect treatment effects on birth weight. Overall, HCA-piglets weighed less at birth, and remained lighter until weaning (P < 0.05). The salivary cortisol concentrations after i.m. injection of ACTH (2.5 IU/kg) were lower in P1- and P3-piglets compared to control piglets. At slaughter, HCA-treatment indirectly decreased lean meat percentage and increased back fat thickness. In conclusion, elevated peripheral cortisol concentrations in pregnant sows affect both litter characteristics and piglet physiology, the latter depending on the period of gestation during which concentrations were elevated. Underlying mechanisms require further investigation.

Differential regulation of agouti-related protein and neuropeptide Y in hypothalamic neurons following a stressful event.

Stress affects eating behaviour in rodents and humans, suggesting that the regulation of energy balance and the stress response are coupled physiological processes. Neuropeptide Y (NPY) and agouti-related protein (AgRP) are potent food-stimulating neuropeptides that are highly co-localised in arcuate nucleus neurons of the hypothalamus. Recent studies have shown that NPY and AgRP mRNA levels in these neurons respond similarly to fasting and leptin, indicating functional redundancy of the neuropeptide systems in these orexigenic neurons. However, we have found that NPY and AgRP mRNA expression in arcuate nucleus neurons are dissociated immediately following a stressful event. Two hours following a brief session of inescapable foot shocks, AgRP mRNA levels are down-regulated (P < 0.0001). In contrast, NPY mRNA levels are up-regulated (P < 0.0001). To provide physiological relevance for this acute down-regulation of AgRP, an inverse agonist of melanocortin receptors, we have shown that acute intracerebroventricular injection of a melanocortin receptor agonist, alpha-melanocyte-stimulating hormone (alpha-MSH), caused a significantly stronger activation of the hypothalamus-pituitary-adrenal-cortical (HPA) axis following a stressful event than in controls. Thus, AgRP and NPY mRNA levels in similar arcuate nucleus neurons are differentially regulated following a stressful event. This may contribute to increased sensitivity for alpha-MSH to activate the HPA axis following a repeated stressful experience.

Long-lasting effects of neonatal dexamethasone treatment on spatial learning and hippocampal synaptic plasticity: involvement of the NMDA receptor complex.

The effects of neonatal dexamethasone (DEX) treatment on spatial learning and hippocampal synaptic plasticity were investigated in adult rats. Spatial learning in reference and working memory versions of the Morris maze was impaired in DEX-treated rats. In hippocampal slices of DEX rats, long-term depression was facilitated and potentiation was impaired. Paired-pulse facilitation was normal, suggesting a postsynaptic defect as cause of the learning and plasticity deficits. Western blot analysis of hippocampal postsynaptic densities (PSD) revealed a reduction in NR2B subunit protein, whereas the abundance of the other major N-methyl-D-aspartate (NMDA) receptor subunits (NR1, NR2A), AMPA receptor subunits (GluR2/3), scaffolding proteins, and Ca2+/calmodulin-dependent protein kinase II (alphaCaMKII) were unaltered. This selective reduction in NR2B likely resulted from altered receptor assembly rather than subunit expression, because the abundance of NR2B in the homogenate and crude synaptosomal fractions was unaltered. In addition, the activity of alphaCaMKII, an NMDA receptor complex associated protein kinase, was increased in PSD of DEX rats. The results indicate that neonatal treatment with DEX causes alterations in composition and function of the hippocampal NMDA receptor complex that persist into adulthood. These alterations likely explain the deficits in hippocampal synaptic plasticity and spatial learning induced by neonatal DEX treatment.

Anxious-retarded depression: relation with plasma vasopressin and cortisol.

Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is related to melancholic or endogenous depression; however, the strength of this relationship depends on the definition of the specific depression subcategory. A two-dimensionally defined subcategory, anxious-retarded depression, is related to melancholic depression. Since arginine vasopressin (AVP) activates the HPA axis, and both major depression and the melancholic subcategory are associated with elevated plasma AVP levels, we investigated whether the plasma AVP level is also elevated in anxious-retarded depression, melancholic depression and anxious-retarded melancholic depression, and whether plasma AVP and cortisol levels are correlated in these subcategories. A total of 66 patients with major depression not using oral contraception were investigated. Patients with anxious-retarded depression had a highly significant AVP-cortisol correlation, while no such correlation was found in patients with nonanxious-retarded depression. Log-transformed mean plasma AVP values were higher in patients with anxious-retarded depression than in patients with nonanxious-retarded depression. Patients with anxious-retarded melancholic depression also had a significantly elevated level of plasma AVP and a highly significant correlation between plasma AVP and cortisol levels. The correlation was low in patients with melancholic depression. Anxious-retarded depression may be a useful refinement of the melancholic subcategory with regard to dysregulation of the HPA axis and plasma AVP release.

Neonatal dexamethasone treatment affects social behaviour of rats in later life.

Synthetic glucocorticoids, like dexamethasone (DEX), have been frequently administered to premature infants to prevent chronic lung disease. Major concern has arisen about the long-term neurodevelopmental sequelae of this DEX treatment. In the present study, we found that neonatal DEX treatment in rats, using a treatment protocol resembling the one used in the clinical situation, increased social play behaviour in juvenile life. Furthermore, neonatal DEX treatment increased sexual motivation and intromission behaviour in the bi-level chamber, decreased submissive behaviour during an aggressive encounter, and impaired social memory in adulthood. These changes in social behaviour are not due to a general behavioural impairment since anxiety behaviour in the elevated plus maze and exploratory activity in the open-field were not affected in DEX rats. In addition, DEX rats showed no alteration in the total duration of social interest or social activity during a social interaction test. These effects of neonatal DEX treatment on behaviour later in life likely result from neurodevelopmental actions of the hormone since we found no differences in received maternal care between DEX and SAL treated pups. Together these results indicate that neonatal treatment with DEX selectively alters aspects of the behavioural response to social challenges. Thus, neonatal DEX treatment may lead to inappropriate interactions with conspecifics later in life. These data therefore warrant investigation of lasting and potentially adverse effects of treatment of human neonates with DEX on social functioning.

Variability factors in the expression of stress-induced behavioural sensitisation.

Altered behavioural and physiological responsivity following a short session of foot shocks in the rat has proven to be a stable and clinically relevant model of stress-induced sensitisation. However, a number of key factors influencing effect size or direction have not previously been reported. Rats underwent a single, 15-min session of foot shocks and were exposed to a variety of novel stressful challenges 1 or 2 weeks later. Sensitised behavioural responses (increased immobility) in preshocked rats remained present over 3 days of repeated exposure to noise stress. In mild novel challenges (open field, empty cage), behavioural sensitisation and defecation was most clearly expressed at the beginning of the dark phase (evening). Higher-arousal challenges (prod, noise) caused increased behavioural inhibition in preshocked rats at all three time points (morning, afternoon, evening). Female preshocked rats showed a different pattern of behavioural and defecation sensitisation than preshocked males. The robustness of the model makes it suitable for further investigations into the mechanisms and vulnerability factors involved in the long-term consequences of stress.

Individual coping characteristics, rearing conditions and behavioural flexibility in pigs.

Several studies suggest that classification of piglets early in life based on the degree of resistance they display in a so-called Backtest may be indicative of their coping style at a later age. In the present study behavioural flexibility was investigated in pigs diverging for Backtest response and housing environment during rearing. Pigs were housed either without a rooting substrate (barren housing, B) or in identical pens enriched with deep straw bedding (enriched housing, E) from birth. During the suckling period piglets were subjected to the Backtest. Each piglet was restrained on its back for 1 min and the resistance (i.e. number of escape attempts) was scored. Pigs classified as 'high-resisting' (HR) or as 'low-resisting' (LR) were subjected to a simple (left/right) spatial discrimination (T-maze) task at 8 weeks of age. The effect of a single, subtle intramaze change was determined after acquisition of the task. In addition, pigs were subjected to reversal learning to assess their ability to modulate established behaviour patterns. Housing and its interaction with Backtest classification influenced the behavioural response to the intramaze change: E pigs were considerably more distracted than B pigs. Housing condition affected LR pigs more than HR pigs, as indicated by the interaction effects on various recorded behaviours. These interactions indicate that behavioural responding of pigs with diverging coping characteristics cannot simply be generalised across rearing conditions. Furthermore, HR pigs were less successful in reversal learning than LR pigs, suggesting that they have a higher propensity to develop inflexible behavioural routines.

Attenuated stress responsiveness in an animal model for neurodevelopmental psychopathological disorders.

Day 7 amygdala-lesioned (D7 AMX) rats have been proposed as a model for neurodevelopmental psychopathological disorders such as schizophrenia. Patients with schizophrenia are sensitive to stress and show an impaired hypothalamic-pituitary-adrenal response to certain stressful stimuli. Therefore, we investigated neuroendocrine and behavioral stress responses in the D7 AMX lesion model. Plasma concentrations of ACTH, corticosterone, and catecholamines were measured in response to foot shock and novelty in D7 and D21 lesioned (AMX) and non-lesioned (SHAM) animals. Behavior was recorded and analyzed afterwards. D7 AMX rats, unlike other rats, had a reduced ACTH response to foot shock and showed less active behavior in response to novelty. Neurodevelopmental dysfunction of target structures of the amygdala is associated with disturbed endocrine and behavioral responses to stress. These data accord with the notion that the D7 amygdala-lesioned rat can function as a neurodevelopmental model with relevance to schizophrenia.

Physiological and behavioural responses to duodenal pain in freely moving rats.

Luminal distention of the intestine can be aversive in humans and laboratory animals, and hypersensitivity to distention is found in functional gastrointestinal disorders. Current animal models either require anaesthesia or acute balloon intubation or use implanted balloons of irritant materials, for which the aversive quality of distention and physiological responses have not been well characterised. We report here that silicone balloon catheters implanted in the duodenum via the stomach have long patency without obvious tissue damage. Balloon inflation in freely moving rats caused passive avoidance learning and classic 'pain' postures, as well as graded cardiovascular responses which can be recorded telemetrically. The method should make long-lasting studies of pharmacological and environmental effects on visceral sensitivity more feasible.

Effects of housing and individual coping characteristics on immune responses of pigs.

The impact of environmental factors on immune responses may be influenced by coping characteristics of the individuals under study. The behavioral response of pigs in a so-called Backtest early in life seems indicative of their coping style at a later age. The present study investigated the effects of housing, barren versus enriched, and coping style, as assessed by Backtest classification, on immune responses of pigs. Pigs were housed either without a rooting substrate (barren housing) or in identical pens enriched with deep straw bedding (enriched housing) from birth. During the suckling period, pigs were subjected to the Backtest. Each pig was restrained on its back for 1 min and the resistance (i.e., number of escape attempts) was scored. Pigs classified as 'high-' or 'low-resisting' (HR and LR, respectively) were immunized with di-nitrophenyl-conjugated keyhole limpet haemocyanin (DNP-KLH) at 9 weeks of age. Blood samples were drawn before immunization (Day 0) and weekly thereafter, until Day 35. KLH-specific lymphocyte proliferation following immunization was higher for HR pigs than for LR pigs. Housing did not affect proliferative responses. Housing and coping style interacted in their effect on KLH-specific humoral immune responses. LR pigs from barren housing showed higher KLH-specific antibody titers than LR pigs from enriched housing. Differently housed HR pigs, however, showed similar antibody titers. These findings support other research indicating that individual coping styles of pigs are reflected in their immune responses. More important, the present study demonstrates that effects of housing on humoral immune responses of pigs may differ for pigs with divergent coping styles.

Increased plasma norepinephrine concentration in psychotic depression.

OBJECTIVE: We previously found psychotic depression (PSDEP) to have positively correlating plasma norepinephrine (NE) and vasopressin (AVP) concentrations. Since central noradrenergic activity and plasma NE concentration are highly correlated, this suggests an increased noradrenergic activation of the hypothalamus-pituitary-adrenal axis. We hypothesize the increased release of NE in PSDEP to be an associated mechanism. METHODS: To test this hypothesis we analyzed the relation between plasma NE and PSDEP in a comparison with non-psychotically depressed patients. Potentially confounding variables were, among others, melancholia and two better validated subcategories in the field of melancholia and endogenous depression, three global dimensions of psychopathology - Emotional Dysregulation, Retardation and Anxiety - smoking habit, and different types of psychotropic and particularly antidepressant treatment. The data from nine patients with PSDEP and 69 patients with non-PSDEP were reanalysed. RESULTS: Analysis of covariance controlling for the effects of tricyclic antidepressant treatment (≥100 mg) and smoking habit showed that PSDEP had an increased concentration of plasma NE. The previously found correlation between plasma NE and AVP was still present after correcting for the effects of confounding variables. CONCLUSIONS: The results suggest an increased activity of the sympathetic nervous system in PSDEP that may act as a specific mechanism for increased vasopressinergic activation. This supports the view of PSDEP as a distinct subcategory of major depression.

Evidence of vasopressinergic-noradrenergic mechanisms in depression with above-normal plasma vasopressin concentration with and without psychotic features.

Previous studies in the field of melancholic or endogenous depression have resulted in support for a subcategory of depression with above-normal plasma vasopressin (AVP) concentration (ANA). Since an analogous animal model with increased release of above-normal plasma vasopressin exhibits reduced Sympathetic-Nervous-System activity, the present study investigated the plasma norepinephrine concentration and the correlation between plasma norepinephrine and AVP in this ANA depression. As psychotic-melancholic patients may have increased plasma norepinephrine concentration, and noradrenergic activation may stimulate AVP release, potentially confounding effects of psychotic features were also investigated. The data set of the same depressed patient sample that was used before, but limited to those with complete hormonal data (n = 75), was re-analysed. ANA depression (n = 14) had negatively correlating AVP and norepinephrine concentrations. A very small subcategory of ANA depression with psychotic features (n = 3) had high plasma norepinephrine concentration, suggesting that this could be an independent subcategory. This was supported by the combination of relatively low above-normal plasma AVP concentrations with the highest severity scores for depression in this subcategory, which does not correspond with the positive correlation between AVP concentration and severity in non-psychotic ANA depression. The results further support the validity of ANA depression and the analogy with the High Anxiety Behaviour animal model of depression. Further investigations are needed to replicate these findings and to search for genetic and traumatic factors involved.