Decreased sensitivity to thermal pain in rats bred for high anxiety-related behaviour is attenuated by citalopram or diazepam treatment

Complex interactions between pain perception, anxiety and depressive symptoms have repeatedly been described. However, pathophysiological or biochemical mechanisms underlying the alterations of pain perception in patients suffering from anxiety or depression still remain a matter of debate. Thus, we aimed to perform an investigation on pain perception in an animal model of extremes in anxiety-related behaviour, which might provide a tool for future studies. Here, thermal pain thresholds were obtained from rats with a genetic predisposition to high anxiety-related behaviour (HAB), including signs of comorbid depression-like behaviour and from controls (low-anxiety rats (LAB); cross-bred HAB and LAB rats; Wistar rats). Furthermore, the effect of eight-week antidepressive treatment using citalopram and of short-term anxiolytic treatment with diazepam on pain-related behaviour was assessed. Simultaneously, anxiety-related behaviour was monitored. At baseline, HAB animals showed 35% higher thresholds for thermal pain than controls. These were normalized to control levels after eight weeks of continuous citalopram treatment paralleled by a reduction of anxiety-related behaviour, but also acutely after diazepam administration. Overall, thermal pain thresholds in HAB animals are shifted in a similar fashion as seen in patients suffering from major depressive disorder. Antidepressive, as well as anxiolytic treatments, attenuated these differences. As the relative importance of the factors anxiety and depression cannot be derived from this study with certainty, extending these investigations to additional animal models might represent a valuable tool for future investigations concerning the interrelations between anxiety, depression, and pain at a molecular level.     

Unconditioned anxiety and social behaviour in two rat lines selectively bred for high and low anxiety-related behaviour

Individuals of high anxiety-related behaviour (HAB) and low anxiety-related behaviour (LAB) rat lines were selectively bred for differences in anxiety-related behaviour on the elevated plus-maze. The goal of this study was to investigate whether this behavioural difference is restricted to the test used as the selection criterion or whether it is a stable and robust trait also in other conflict or non-conflict situations. Therefore, behaviour of male and female HAB and LAB rats was examined in two further tests of unconditioned anxiety: the black-white box and the social interaction test. Furthermore, behaviour of group-housed male HAB and LAB rats was studied in their home cages. In addition to standard statistics, discriminant analyses were performed. The difference in anxiety-related behaviour between the two lines was highly consistent in all tests of unconditioned anxiety. There were also differences in home cage behaviour, LAB rats being more active than HAB rats; this is likely to be a consequence of the LAB rats displaying a higher aggressiveness in social behaviour, compared to HAB rats. In all tests used HAB and LAB rats were clearly distinguished by discriminant analysis. However, while in the elevated plus-maze and the black-white box test the most important parameters for discrimination between the two lines were mainly those generally seen as closely related to anxiety, the discrimination in the social interaction paradigm was primarily due to differences in locomotor activity.     

The rostral anterior cingulate cortex modulates depression but not anxiety-related behaviour in the rat

A growing body of functional imaging studies suggests that human depression and anxiety symptoms are associated with functional abnormalities in the circuitry formed by the rostral anterior cingulate cortex (rACC) and its direct limbic and paralimbic connections. In rodents however, the role of the rACC (rCG1/rCG2) remains unknown in depression-related behaviours and elusive in acute anxiety. In order to address this, we specifically lesioned the rat rCG1/rCG2, and assessed the behavioural outcome using a modified forced swim test (FST) and the elevated plus maze (EPM), tests for depression and anxiety related behaviours respectively. Lesions of the rostral anterior cingulate cortex significantly increased the time spent immobile in the FST without affecting climbing or swimming performances, suggesting a pro-depressant effect. On the contrary, none of the parameters measured in the EPM was affected by the lesion. These data point to an involvement of the rCG1/rCG2 in depression-related coping behaviours.     

Disruption to social dyadic interactions but not emotional/anxiety-related behaviour in mice with heterozygous 'knockout' of the schizophrenia risk gene neuregulin-1

Clinical genetic studies have implicated neuregulin-1 [NRG1] as a leading susceptibility gene for schizophrenia. NRG1 is known to play a significant role in the developing brain, which is consistent with the prevailing neurodevelopmental model of schizophrenia. Thus, the emotional and social phenotype of adult mice with heterozygous 'knockout' of transmembrane [TM]-domain NRG1 was examined further in both sexes. Emotional/anxiety-related behaviour was assessed using the elevated plus-maze and the light-dark test. Social behaviour was examined in terms of dyadic interactions between NRG1 mutants and an unfamiliar C57BL6 conspecific in a novel environment. There was no effect of NRG1 genotype on performance in either test of emotionality/anxiety. However, previous reports of hyperactivity in NRG1 mutants were confirmed in both paradigms. In the test of social interaction, aggressive following was increased in NRG1 mutants of both sexes, together with an increase in walkovers in female mutants. These findings elaborate the specificity of the NRG1 phenotype for the social rather than the emotional/anxiety-related domain. They indicate that NRG1 is involved in the regulation of reciprocal social interaction behaviour and thus suggest a putative role for NRG1 in a schizophrenia-related endophenotype.     

Is antidepressant efficacy revealed by drug-induced changes in rat behaviour exhibited during social interaction?

Remission from depressive illness is associated with a modification in patients' behavioural reactions to environmental/social stimulation, and requires continuous drug treatment. We have examined the effects of antidepressant drug treatment and repeated electroconvulsive shock (ECS) on the behaviour of rats during social interaction (SI) to determine whether antidepressant treatments modify behavioural patterns of experimental animals that may be related to their ability to modify reactive human behaviour. Acute treatment of short-term isolated resident rats with nonsedative doses of antidepressant drugs, or sedative doses of haloperidol and diazepam, dose relatedly reduced aggressive behaviour exhibited during SI. Conversely, chronic antidepressant treatment (including ECS), but not chronic haloperidol or diazepam treatment, increased the aggressive behaviour of resident rats. These studies have revealed selective, diametrically opposite, effects of acute and chronic antidepressant treatment on rodent aggressive behaviour that may be indicative of antidepressant efficacy. The effects of chronic antidepressant treatment in particular may indicate a disinhibition of rodent social behaviour which may mirror the externalisation of emotions associated with the remission of depressive illness.     

Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice

The arginine vasopressin (AVP) system plays an important role in social behavior. Autism, with its hallmark disturbances in social behavior, has been associated with the V1a receptor (V1aR) gene. Furthermore, impairments of social function are often observed in symptoms of schizophrenia. Subchronic phencyclidine (PCP) produces behaviors relating to certain aspects of schizophrenic symptoms such as impairing social interaction in animals and it reduces the density of V1aR binding sites in several brain regions. Here, we report that V1aR knockout (KO) mice exhibited impairment of social behavior in a social interaction test, and showed reduced anxiety-related behavior in elevated plus-maze and marble-burying behavior tests. Given the current findings, the V1aR may be involved in the regulation of social interaction, and V1aR KO mice could be used as an animal model of psychiatric disorders associated with social behavior deficits, such as autism and schizophrenia.     

Decreases in dilated pupil size in depressed patients with age may reflect adrenergic changes

Some studies have suggested that noradrenergic activity may decrease with age in depressed patients. Pupil size is regulated by a balance between norepinephrine and acetylcholine. The present study compares pupil size in 10 unmedicated patients with unipolar depression (296. 3) and in 16 normal controls. Pupil size after dilation with tropicamide, a cholinergic antagonist, was inversely related to age in the patients (r=-0.87), but did not diminish with age in controls. The results suggest that pupil size may provide an index of diminished noradrenergic function with age in patients with major depression.     

Isolation changes the incentive value of sucrose and social behaviour in juvenile and adult rats

The present study was undertaken to assess the motivational aspects of social behaviour in juvenile and adult rats using the conditioned place preference (CPP) test and anticipatory behaviour for social contact. In addition, the consequences of social isolation during different periods of age on the motivational properties of sucrose-drinking and adult social behaviour were studied. Social play and adult social contact could be used as incentives for place preference conditioning and for inducing conditioned hyperactivity (anticipation) in rats. Both social activities have motivational properties for individually housed rats, whereas group-housing dramatically reduced the motivational aspects of adult social contact. In contrast, sucrose-drinking appears to have motivational aspects independent of the housing condition. Adult social behaviour could not induce a CPP in juvenile isolated rats, suggesting that juvenile isolation during 4 5 weeks reduced the motivational aspects of adult social contact. It seems likely that no CPP was established as a result of the reduced level of social behaviour during the conditioning sessions. Additionally, juvenile isolation during 4-5 weeks appeared to also decrease the motivational properties of sucrose-drinking in maturity, because the intensity of anticipation in response to sucrose was significantly suppressed. Thus, the data suggest that juvenile isolation during 4-5 weeks decreases the motivational properties of both social contact and sucrose-drinking in later life.     

Kindling with the beta-carboline FG7142 suggests separation between changes in seizure threshold and anxiety-related behaviour

The aim of this paper was to determine whether the prolonged decrease in seizure threshold produced by chemical kindling was accompanied by behavioural changes in tests of anxiety and aggression. The responses of rats in five tests were examined after chronic treatment with the benzodiazepine inverse agonist FG7142. This treatment caused chemical kindling, so that the originally proconvulsant drug caused full seizures. This effect is very long-lasting, and our previous work with mice had suggested that it might be accompanied by an increase in anxiety-related behavior. In the present work no significant differences were found between the behaviour of FG7142-kindled rats and vehicle-treated controls in social interaction test, elevated plus maze, or the Vogel conflict test of anxiety or in tests of home cage aggression or startle responses. The results therefore show that prolonged changes in seizure threshold can occur without alterations in the apparent level of anxiety.     

The reciprocal interaction between serotonin and social behaviour

Serotonin (5-HT) is an ancient molecule directing behavioural responses to environmental stimuli. The social environment is the most powerful environmental factor. It is well recognized that 5-HT plays a key role in shaping social responses, and that the serotonergic system itself is highly responsive to social influences. This review aims to provide an overview of a selection of representative papers that significantly contribute to a coherent view on the role of serotonin in reciprocal social interactions. The studies here reviewed, selected using the pubmed search terms "social behaviour" and "serotonin", describe the effects of serotonergic gene variation and pharmacological manipulations in humans, monkeys, and rodents, and involve parental attachment and caregiving, social play, aggressiveness, cooperation, and sexual behaviour. We conclude that serotonin is positively correlated with sensitivity to social factors and modulates social behaviour in a 'for-better-and-for-worse' manner, depending on the nature of social factors. Simultaneously, these behavioural responses influence the serotonergic system, leading to highly complex bidirectional serotonin×environment interaction.     

C-type natriuretic peptide exerts effects opposing those of atrial natriuretic peptide on anxiety-related behaviour in rats

As evidence exists that C-type natriuretic peptide (CNP) exerts effects opposing those of atrial natriuretic peptide (ANP), we studied the behavioural properties of CNP after central infusion in rats by their performance in the elevated plus maze. Doses of 0.5 μg and 5 μg i.c.v. had distinct anxiogenic properties. Our data suggest opposing effects of CNP and ANP on anxiety-related behaviour in rats, which appear to be mediated via different receptor occupation and brain regions by a corticotropin-releasing hormone (CRH)-dependent mechanism.     

Perinatal hypothyroidism effects on neuromotor competence,novelty-directed exploratory and anxiety-related behaviour and learning in rats

Thyroid hormone is essential for proper development of the mammalian CNS. Previous studies have documented a decrease in the ability of neonatal hypothyroid animals to learn and to habituate to maze tests and an increase in spontaneous activity. However, there is little information about the effects of perinatal (i.e. perinatal and postnatal) hypothyroidism on behaviour. The aim of the present work was to investigate the longitudinal effects of perinatal hypothyroidism on certain aspects of the behaviour in rats. Neuromotor competence was tested at 21, 40 and 60 days, novelty-directed exploratory behaviour and anxiety-related behaviour were evaluated at 40 and 60 days by means of the Boissier tests and associative learning ability was tested at 80 days by means of a step-through passive avoidance task. The persistence of the effects of perinatal hypothyroidism on psychomotor performance was highly dependent on the task examined. Perinatal hypothyroidism caused an increase of locomotor activity as revealed by the total distance travelled in the Boissier test and this increase also comprised a component of decreased anxiety-related behaviour. Methimazole-treated subjects also had higher head-dip scores than controls at 40 days while no differences were observed at 60 days. Finally, our results showed that methimazole-treated rats performed poorly in a passive avoidance learning task.     

Decreased CSF-beta-amyloid 42 in Alzheimer's disease and amyotrophic lateral sclerosis may reflect mismetabolism of beta-amyloid induced by disparate mechanisms

Both tau and beta-amyloid 42 (Abeta42) have been implicated in Alzheimer's disease (AD) and tau alone in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). These proteins can be measured in the cerebrospinal fluid (CSF); differences from normal CSF levels may reflect pathophysiological mechanisms. Using ELISAs, we investigated the levels of total CSF-tau (here referred to as tau), phosphorylated CSF-tau (phosphotau), and Abeta42 in patients with AD (n = 19), FTD (n = 14), ALS (n = 11) and Parkinson's disease (PD; n = 15) and in age-matched controls (n = 17). Both CSF-tau and CSF-phosphotau were increased in AD compared with FTD (p < 0.001), ALS (p < 0.001), PD (p < 0.001) and controls (p < 0.001). CSF-Abeta42 was markedly decreased in AD and ALS (both p < 0.001) and slightly decreased in FTD (p < 0.01) and PD (p < 0.05) compared with controls. Using CSF-phosphotau may improve the differentiation of AD from FTD and ALS in clinical praxis. Furthermore, decreased CSF-Abeta42 levels may be common in neurodegenerative disorders possibly reflecting changes in the metabolism of beta-amyloid or axonal degeneration.     

Regular voluntary exercise reduces anxiety-related behaviour and impulsiveness in mice

We embarked on a study to delineate the behavioural changes in mice after 4 weeks of voluntary exercise. As an initial behavioural characterization, we exposed the control and exercising mice to a modified hole board and an open field test. As compared to control mice, exercising animals showed clear signs of increased behavioural inhibition (e.g. a longer latency to enter unprotected areas), suggesting increased anxiety in these animals. In addition, the exercising mice were reluctant to spend time in the open field's centre during the beginning of the 30-min open field test, but compensated for this at later times. Paradoxically, the exercising animals showed more rearings on the board of the modified hole board, indicating decreased anxiety. Thus, the behavioural inhibition seen in exercising mice is likely to represent decreased stress responsiveness at the behavioural level which can also be interpreted as reduced impulsiveness. To clarify whether voluntary exercise evolves in more or less anxiety-related behaviour, we exposed animals to the elevated plus-maze and the dark-light box, two selective tests for unconditioned anxiety. Clearly, compared to the control animals, exercising mice spent significantly more time on the open arm of the plus-maze and spent double the amount of time in the light compartment of the dark-light box. Taken together, we conclude that long-term voluntary exercise appears to result in decreased anxiety-related behaviour and impulsiveness. Thus, our observations fit into the concept that regular exercise strengthens endogenous stress coping mechanisms, thereby protecting the organism against the deleterious effects of stress.     

Evidence that oxidative stress is linked to anxiety-related behaviour in mice

Oxidative stress in central and peripheral systems is involved in many diseases, including cancer, cardiovascular diseases, neurodegenerative diseases and several psychiatric disorders. In the present study, the brain and peripheral oxidative status of non-anxious and anxious mice was evaluated using 2′,7′-dichlorofluorescin diacetate (DCFH-DA), a sensor of reactive oxygen species (ROS). Here we report that anxiety levels are linked to the oxidative status in both neuronal and glial cells in the cerebellum and hippocampus, in neurons of the cerebral cortex and in peripheral leucocytes (monocytes, granulocytes and lymphocytes), revealing the presence of oxidative stress in the central and peripheral systems of anxious mice. These findings suggest the redox system in anxious mice may play a role in neuroinflammation and neurodegeneration, predisposing them to recurrent infections and chronic inflammation.     

Multidimensional structure of anxiety-related behavior in early-weaned rats

Early environmental stimuli affect various aspects of physical and behavioral development. Weaning is one of the most important events in the early stage of life, and recently we have found that precocious weaning augments anxiety and aggressiveness in mice. Here, we report the presence of virtually identical phenomena in rats. To understand the multidimensional structure of anxiety-related behavior, the influence of early weaning upon behavior in adulthood was investigated using three behavioral tests: the elevated plus-maze test, the hole-board test and the open-field test. Two groups of rats were prepared. One was weaned from the dam at 16 days of age (early-weaned group) and the other at 30 days (normally weaned group) as a control. Both groups were subjected to the three tests at 8-10 weeks of age. The elevated plus-maze test revealed lower frequency of entry to and shorter duration of stay in the open arms in the early-weaned animals. In the hole-board test, the early-weaned rats showed lower frequency and shorter duration of head dipping into the holes. And in the open-field test, the early-weaned rats tended to stay at the central square for a shorter period and to defecate more frequently. The behavioral parameters of the three tests were combined and subjected to principal component analysis (PCA). The factorial scores for six extracted factors were compared between the early-weaned and normally weaned groups, and it was revealed that the early-weaned rats had a lower score in Factor 1 (non-anxious exploration) and Factor 5 (risk assessment behavior). Taken together, these results suggest that the time of weaning had a considerable impact on behavioral development, particularly with respect to anxiety-related behaviors.