Effects Of Social Defeat Research Articles

Voluntary wheel running during adolescence prevents the increase in ethanol intake induced by social defeat in male mice.

Exposure to social defeat (SD) induces a depressive phenotype, increased ethanol seeking and consumption, accompanied by activation of the neuroinflammatory response. However, a resilient response can be potentiated through physical exercise in the form of voluntary wheel running (VWR) during or after exposure to social stress. Therefore, the aim of this study was to test whether physical exercise during adolescence prior to being exposed to SD can enhance resilience to the increase in ethanol intake. Male mice had access to VWR during adolescence and the effects of social defeat (4 sessions every 72h) on oral ethanol self-administration (SA) was evaluated. Based on the social interaction test, mice were classified as resilient or susceptible to depressive-like behavior. Two weeks after the last encounter, mice were subjected to the drinking in the dark and oral ethanol SA paradigms. Mice were then sacrificed to measure brain-derived neurotrophic factor (BDNF) levels in the striatum and hippocampus. As expected, susceptible mice increased ethanol intake in the oral SA protocol. However, susceptible mice in the exercise condition did not increase ethanol intake, showing similar consumption and motivation for ethanol than the control and resilient groups. On the other hand, decreased BDNF levels were observed in susceptible mice in both experimental conditions compared to the control groups after ethanol SA. The pre-exposure of VWR prevented the increase in consumption and motivation for ethanol induced by SD in susceptible mice. On the other hand, it appears that VWR did not exhibit any significant long-term effects on BDNF signaling, which is mainly affected in susceptible mice after ethanol intake.

Effects of Social Defeat on Hippocampal CA1 Neuronal and Sympathetic Nerve Activities in Conscious Rats

Social defeat stress has been linked to depression, autonomic disorders, and cardiovascular disorders. The hippocampus has been implicated in the pathogenesis of depression, and hippocampal neuronal activity is presumed to be involved in autonomic disorders induced by social defeat stress. Potential linkages among hippocampal neuronal activities, sympathetic nerve activities, and cardiovascular function have received less attention. In the present study, we measured time courses of changes in hippocampal CA1 neuronal activity (CA1NA), renal sympathetic neuronal activity (RSNA), and lumbar sympathetic nerve activity (LSNA), arterial pressure (AP), and heart rate (HR) in response to social defeat stress in rats. Wistar rats were chronically implanted with electrodes for the measurement of CA1NA, RSNA, LSNA; electroencephalography, cervical electromyography, and diaphragm electromyography were performed, and a catheter was used to measure AP. Social defeat was induced by introduction of a Long–Evans rat, which was heavier and more aggressive than a Wistar rat, into the Wistar rat’s home cage for 30 minutes. The intrusion of the Long–Evans rat sometimes resulted in fighting between the Long–Evans and Wistar rats. Following defeat, Wistar rats displayed a submissive posture and exhibited immobilization for several minutes. Fighting caused immediate reduction of CA1NA, which remained suppressed during the period of submissive posture and immobilized behavior. However, the AP, HR, RSNA, and LSNA increased in transient fashion during immobilized behavior. These findings showed that the defeat stress considerably influenced CA1NA, whereas it marginally influenced RSNA, LSNA, AP, and HR. Therefore, it is likely that social defeat stress suppressed hippocampal function in tonic fashion, which could not be measured on the basis of sympathetic nerve activity and cardiovascular function.Support or Funding InformationJSPS Grant

Serotonin Signaling Trough Prelimbic 5-HT1A Receptors Modulates CSDS-Induced Behavioral Changes in Adult Female Voles

BackgroundMost previous studies have focused on the effects of social defeat in male juvenile individuals. Whether chronic social defeat stress in adulthood affects female emotion and the underlying mechanisms remains unclear.MethodsUsing highly aggressive adult female mandarin voles (Microtus mandarinus), the present study aimed to determine the effects of chronic social defeat stress on anxiety- and depression-like behaviors in adult female rodents and investigate the neurobiological mechanisms underlying these effects.ResultsExposure of adult female voles to social defeat stress for 14 days reduced the time spent in the central area of the open field test and in the open arms of the elevated plus maze and lengthened the immobility time in the tail suspension and forced swimming tests, indicating increased anxiety- and depression-like behaviors. Meanwhile, defeated voles exhibited increased neural activity in the prelimbic cortex of the medial prefrontal cortex. Furthermore, chronic social defeat stress reduced serotonin projections and levels of serotonin 1A receptors in the medial prefrontal cortex-prelimbic cortex. Intra-prelimbic cortex microinjections of the serotonin 1A receptor agonist 8-OH-DPAT reversed the alterations in emotional behaviors, whereas injections of the serotonin 1A receptor antagonist WAY-100635 into the prelimbic cortex of control voles increased the levels of anxiety- and depression-like behaviors.ConclusionsTaken together, our results demonstrated that chronic social defeat stress increased anxiety- and depression-like behaviors in adult female voles, and these effects were mediated by the action of serotonin on the serotonin 1A receptors in the prelimbic cortex. The serotonin system may be a promising target to treat emotional disorders induced by chronic social defeat stress.

Role of NMDA and AMPA glutamatergic receptors in the effects of social defeat on the rewarding properties of MDMA in mice.

Exposure to social stress alters the response to drugs of abuse of experimental animals. Changes in the glutamatergic system seem to play a role in the effects of social defeat stress on the rewarding properties of cocaine and amphetamine. The aim of the present study was to evaluate the involvement of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors in the effects of social defeat on the conditioned place preference induced by 3,4-methylenedioxymethamphetamine (MDMA). Our hypothesis was that changes in these receptors could mediate the effects of social defeat on MDMA reward. Young adult male mice were exposed to an episode of social defeat with an aggressive conspecific immediately before each conditioning session with MDMA (1.25mg/kg, four sessions on alternating days). According to the treatment received before defeats, six groups were used: saline, 5 or 10mg/kg of memantine (NMDA antagonist) and 0.25, 1 or 5mg/kg of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (AMPA antagonist). One control group was exposed to exploration before place conditioning. In two additional defeated and control groups, the membrane expression of NMDA and AMPA receptors was determined in the striatum and the hippocampus. Control and memantine-treated groups developed place preference, but not defeated mice treated with saline or CNQX, suggesting that the blockade of NMDA receptors reversed the effects of social defeat. Social defeat decreased the expression of several subunits of NMDA and AMPA receptors, mainly GluN1 and GluA1. These results demonstrated that glutamatergic plasticity is involved in the effects of social defeat stress on MDMA reward.

Microglial Over-Activation by Social Defeat Stress Contributes to Anxiety- and Depressive-Like Behaviors.

Hyper activation of the neuroimmune system is strongly related to the development of neuropsychiatric disorders. Psychosocial stress has been postulated to play an important role in triggering anxiety and major depression. In preclinical models, there is mounting evidence that social defeat stress activates microglial cells in the central nervous system. This type of stress could be one of the major factors in the development of these psychopathologies. Here, we reviewed the most recent literature on social defeat and the associated immunological reactions. We focused our attention on microglial cells and kept the effect of social defeat over microglia separate from the effect of this stressor on other immune cells and the influence of peripheral immune components in priming central immune reactions. Furthermore, we considered how social defeat stress affects microglial cells and the consequent development of anxiety- and depressive-like states in preclinical studies. We highlighted evidence for the negative impact of the over-activation of the neuroimmune system, especially by the overproduction of pro-inflammatory mediators and cytotoxins. Overproduction of these molecules may cause cellular damage and loss or decreased function of neuronal activity by excessively pruning synaptic connections that ultimately contribute to the development of anxiety- and depressive-like states.

Adolescent Social Defeat Induced Alterations in Social Behavior and Cognitive Flexibility in Adult Mice: Effects of Developmental Stage and Social Condition.

Negative social experiences during adolescence increase the risk of psychiatric disorders in adulthood. Using “resident-intruder” stress, the present study aimed to investigate the effects of adolescent social defeat on emotional and cognitive symptoms associated with psychiatric disorders during adulthood and the effects of the developmental stage and social condition on this process. In Experiment 1, animals were exposed to social defeat or manipulation for 10 days during early adolescence (EA, postnatal days [PND] 28–37), late adolescence (LA, PND 38–47), and adulthood (ADULT, PND 70–79) and then singly housed until the behavioral tests. Behaviors, including social avoidance of the defeat context and cortically mediated cognitive flexibility in an attentional set-shifting task (AST), were assessed during the week following stress or after 6 weeks during adulthood. We determined that social defeat induced significant and continuous social avoidance across age groups at both time points. The mice that experienced social defeat during adulthood exhibited short-term impairments in reversal learning (RL) on the AST that dissipated after 6 weeks. In contrast, social defeat during EA but not LA induced a delayed deficit in extra-dimensional set-shifting (EDS) in adulthood but not during adolescence. In Experiment 2, we further examined the effects of social condition (isolation or social housing after stress) on the alterations induced by social defeat during EA in adult mice. The adult mice that had experienced stress during EA exhibited social avoidance similar to the avoidance identified in Experiment 1 regardless of the isolation or social housing after the stress. However, social housing after the stress ameliorated the cognitive flexibility deficits induced by early adolescent social defeat in the adult mice, and the social condition had no effect on cognitive function. These findings suggest that the effects of social defeat on emotion and cognitive function are differentially affected by the developmental stage and social condition. EA may comprise a particularly sensitive developmental period in which social defeat may produce a delayed impairment in cognitive flexibility during adulthood, and the social condition following stress appears to play an important intermediary role in the development of these cognitive deficits.

The effects of social defeat on behavior and dopaminergic markers in mice

The present study investigated the effects of chronic social defeat stress on several behavioral parameters, and the expression of dopaminergic markers, i.e., dopamine D1 receptors (D1Rs), dopamine D2 receptors (D2Rs), and dopamine and cyclic adenosine 3′,5′-monophosphate-regulated phosphoprotein-32 (DARPP-32), in the prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HIP) of mouse brains. After 10days of social defeat stress, the defeated mice were divided into two groups: one group underwent a series of behavioral tests. The other group was sacrificed on the 11th day and tissue samples were collected for Western blotting. The behavioral tests comprised tests of locomotion, light/dark preference, social interaction, as well as the novel object recognition test (NORT), Morris water maze, and forced swimming test (FST). We measured the expression of D1Rs, D2Rs, total DARPP-32, phospho-Thr34 or Thr75-DARPP-32 using Western blotting. The defeated mice showed increased anxiety- and depression-like behaviors, and impaired cognition. No significant differences in D1Rs and D2Rs expression were shown between defeated and control mice in any area studied. A significantly increased expression in total DARPP-32, and phospho-DARPP-32 was observed in the PFC or AMY of defeated mice. These data suggest that alterations in dopaminergic markers may be involved in anxiety- and depression-like behaviors, and cognitive impairment induced by social defeat stress.

Long-lasting effects of social defeat on spatial learning and hystone acetylation in the hippocampus

Long-lasting effects of social defeat on spatial learning and hystone acetylation in the hippocampus

Effects of acute social stress on the conditioned place preference induced by MDMA in adolescent and adult mice.

Exposure to social defeat stress increases the rewarding effects of psychostimulants in animal models, but its effect on 3,4-methylenedioxymethylamphetamine (MDMA) reward has received little attention. In the present study, we evaluated the influence of social defeat on the rewarding effects of MDMA in adolescent [postnatal day (PND) 29-40] and adult (PND 50-61) male mice using the conditioned place preference paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1.25 or 10 mg/kg of MDMA. The effects of social defeat on corticosterone levels and the motor or the anxiogenic effects of MDMA were also evaluated. Mice exposed to social defeat during adulthood did not show conditioned place preference after conditioning with either dose of MDMA. Conversely, social defeat did not affect the anxiogenic and motor effects of MDMA. Adult mice exposed to social defeat showed higher levels of corticosterone than their controls and adolescent mice. Social stress did not induce behavioural effects in adolescent mice. Our results show that stress induced by social defeat decreases the sensitivity of adult mice to the rewarding effects of MDMA.

A low-cost automated apparatus for investigating the effects of social defeat in Syrian hamsters

We describe an automated apparatus that can be used to investigate the effects of defeat in hamsters. It consists of a covered alleyway that leads to a box, or arena, where hamsters can be kept separate or allowed to fight. The alleyway is divided into seven equal-sized chambers. Low-power lasers and laser detectors are used to keep track of a hamster's position in the alleyway. A CFL flood lamp placed over the chamber farthest from the arena generates a light gradient in the alleyway that engenders in the subjects a preference for the darker chambers near the arena. A computer automatically records the interruption of the laser beams and yields three measures: average position, the frequency of visits to each chamber, and the frequency of changes in direction of travel in each chamber. The results of a pilot study indicated that when a dominant hamster was placed behind a screened gate in the arena and a subordinate hamster was placed in the alleyway, the subordinate maintained a significantly greater distance from the dominant than did a nondefeated hamster. The subordinate hamster also changed its direction of travel more frequently than did the nondefeated hamster. The results suggest that conditioned fear was elicited in the defeated hamster by proximity to the dominant hamster, an effect that is consistent with published results in which the data were recorded manually or by using commercially available event-tracking software.

Effects of social defeat on sleep and behaviour: Importance of the confrontational behaviour

We studied the short- and long-term effects of a double social defeat (SD) on sleep parameters, EEG power, behaviour in the open field emergence test, corticosterone responsiveness, and acoustic startle responses. Pre-stress levels of corticosterone were assessed before all rats were surgically implanted with telemetric transmitters for sleep recording, and allowed 3weeks of recovery. Rats in the SD group (n=10) were exposed to 1hour SD on two consecutive days, while control rats (n=10) were left undisturbed. Telemetric sleep recordings were performed before SD (day −1), day 1 post SD, and once weekly for 3weeks thereafter. The open field emergence test was performed on day 9 and weekly for 2weeks thereafter. Blood samples for measures of corticosterone responsiveness were drawn after the last emergence test (day 23). Acoustic startle responses were tested on day 24 post SD. Overall, SD rats as a group were not affected by the social conflict. Effects of SD seemed, however, to vary according to the behaviours that the intruder displayed during the social confrontation with the resident. Compared to those SD rats showing quick submission (SDS, n=5), SD rats fighting the resident during one or both SD confrontations before defeat (SDF, n=5) showed more fragmented slow wave sleep, both in SWS1 and SWS2. They also showed longer latency to leave the start box and spent less time in the open field arena compared to SDS rats. In the startle test, SDF rats failed to show response decrement at the lowest sound level. Our results indicate that how animals behave during a social confrontation is more important than exposure to the SD procedure itself, and that rapid submission during a social confrontation might be more adaptive than fighting back.

Effects of social defeat on sleep and behavior: Importance of the confrontational behavior

We studied the short- and long-term effects of a double social defeat (SD) on sleep architecture, EEG power and behavior. A few studies have shown that rats that fight back or oppose the resident during the social conflict seem less affected by the defeat than those that show quick submission and passivity. Our hypothesis was that rats showing rapid submission in the social defeat would exhibit the most pronounced alterations in sleep architecture and behavior. All rats were surgically implanted with telemetric transmitters for sleep recording. Rats in the SD group ( n = 10) were exposed to 1 h SD on two consecutive days, while control rats ( n = 10) were left undisturbed. Telemetric sleep recordings were performed before SD (day −1), day 1, day 14 and day 21 post SD. The open field emergence test was performed on day 9, day 16 and day 23. Acoustic startle responses were tested on day 24. Overall, SD rats as a group were not affected, neither short-term nor long- term, by the social conflict with regard to sleep architecture, EEG power or behavior. Effects of SD seemed to vary according to the behaviors that the intruder displayed during the confrontation with the resident. Compared to those SD rats showing quick submission (SDS, latency to defeat: 56 ± 20 s, n = 5), SD rats fighting the resident during one or both SD confrontations before defeat (SDF rats, latency to defeat: 158 ± 45 s, n = 5) showed more fragmented SWS, both in SWS1and SWS2 ( p < 0.05, both) at day 1. This effect became more robust after day 14 ( p < 0.05 and p < 0.01, respectively) and day 21 ( p < 0.01, both). Descriptively, SDS and SDF rats showed different sleep architecture prior to SD. SDF rats were less awake, had more SWS2, less SWS1, and more REM sleep. The pattern of differences in SWS1 and SWS2 was maintained throughout the experiment, suggesting that this might reflect a trait rather than an effect of social conflict. REM sleep descriptively increased in the SDS group compared to their own baseline prior to SD on day 1 and day 14. The change across days was not seen in SDF rats. In the emergence test, SDF rats showed longer latency to leave the start box at day 23 ( p < 0.05) and spent less time in the arena compared to those showing quick submission and passivity at day 16 and day 23 ( p < 0.05, both). The SDF rats failed to show response decrement in the startle test at the lowest sound level ( p < 0.01). Our results indicate that aggressivity in a social conflict induces chronic fragmented sleep. A rapid submission during a social confrontation induces less sleep change and this behavior might reflect greater flexibility and to be more adaptive than fighting back. University of Bergen and Norwegian Competence Center for Sleep Disorders.

Glucocorticoids Orchestrate Divergent Effects on Mood through Adult Neurogenesis

Both social defeat stress and environmental enrichment stimulate adrenal glucocorticoid secretion, but they have opposing effects on hippocampal neurogenesis and mood. Hypothalamic-pituitary-adrenal axis dysregulation and decreased neurogenesis are consequences of social defeat. These outcomes are correlated with depressive states, but a causal role in the etiology of depression remains elusive. The antidepressant actions of environmental enrichment are neurogenesis-dependent, but the contribution of enrichment-elevated glucocorticoids is unexplored. Importantly, for both social defeat and environmental enrichment, how glucocorticoids interact with neurogenesis to alter mood is unknown. Here, we investigate causal roles of glucocorticoids and neurogenesis in induction of depressive-like behavior and its amelioration by environmental enrichment in mice. By blocking neurogenesis and surgically clamping adrenal hormone secretions, we showed that neurogenesis, via hypothalamic-pituitary-adrenal axis interactions, is directly involved in precipitating the depressive phenotype after social defeat. Mice adrenalectomized before social defeat showed enhanced behavioral resiliency and increased survival of adult-born hippocampal neurons compared with sham-operated defeated mice. However, mice lacking hippocampal neurogenesis did not show protective effects of adrenalectomy. Moreover, glucocorticoids secreted during environmental enrichment promoted neurogenesis and were required for restoration of normal behavior after social defeat. The data demonstrate that glucocorticoid-dependent declines in neurogenesis drive changes in mood after social defeat and that glucocorticoids secreted during enrichment promote neurogenesis and restore normal behavior after defeat. These data provide new evidence for direct involvement of neurogenesis in the etiology of depression, suggesting that treatments promoting neurogenesis can enhance stress resilience.

The Effect of Social Defeat on Tyrosine Hydroxylase Phosphorylation in the Rat Brain and Adrenal Gland

Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, is regulated acutely by protein phosphorylation and chronically by protein synthesis. No studies have systematically investigated the phosphorylation of these sites in vivo in response to stressors. We specifically investigated the phosphorylation of TH occurring within the first 24 h in response to the social defeat stress in the rat adrenal, the locus coeruleus, substantia nigra and ventral tegmental area. Five groups were investigated; home cage control (HCC), two groups that underwent social defeat (SD+) which were sacrificed either 10 min or 24 h after the end of the protocol and two groups that were put into the cage without the resident being present (SD-) which were sacrificed at time points identical to the SD+. We found at 10 min there were significant increases in serine 40 and 31 phosphorylation levels in the locus coeruleus in SD+ compared to HCC and increases in serine 40 phosphorylation levels in the substantia nigra in SD+ compared to SD-. We found at 24 h there were significant increases in serine 19 phosphorylation levels in the ventral tegmental area in SD+ compared to HCC and decreases in serine 40 phosphorylation levels in the adrenal in SD+ compared to SD-. These findings suggest that the regulation of TH phosphorylation in different catecholamine-producing cells varies considerably and is dependent on both the nature of the stressor and the time at which the response is analysed.

Tail skin temperatures reflect coping styles in rats

This study was carried out to elucidate the predictive value of tail skin temperatures (TSTs) assessed in naïve rats as a non-invasive pre-experimental method of classification of coping style. Male Lewis rats were classified according to tail skin temperatures (TST), and relative size within cage-groups. TSTs were monitored over two-hour periods following exposure to physical and emotional stressors. Bodyweight-shifts associated to the experiments were analysed. Six organs of neuroendocrine relevance to allostasis were weighed. Challenge-specific TST-profiles were size-related and consistent with proactive or reactive coping. Pro-active (A) rats showed a more pronounced TST-response to unknown conspecifics, but reactive (B) rats to environmental novelties. B-rats showed challenge-specific weight-losses while A-rats gained more after experiments. Second size males showed rapidly decreased TSTs (vasoconstriction) after nociceptive stimulation. Males that showed the highest basal TSTs and weight-loss in emotionality tests had lost a first rank position during a pre-experimental period, suggesting long-lasting effects of social defeat. Pre-experimental growth correlated positively to adiposisity post-experimentally, but negatively to testes relative weight in B-rats. Scaling effects explained heart-size in B-rats and pituitary-size in A-rats. The overall patterns that emerged, in factor analyses including organ sizes, were consistent with pro-active coping in A-rats and reactive in B-rats. Our results, controlling for rank-effects, suggest that non-invasively assessed TSTs may predict individual stress-coping phenotypes pre-experimentally in rats housed in groups.

P.2.28 Chronic imipramine treatment partly reverses behavioral effects of social defeat in rats

P.2.28 Chronic imipramine treatment partly reverses behavioral effects of social defeat in rats

Non-specific Effect of Fear Conditioning and Specific Effect of Social Defeat on Social Recognition Memory Performance in Female Rats

The so called “emotion learning” literature describes the ability of distressing and aversive unconditioned stimuli to classically condition a learned avoidance response. In order to investigate the impact of experience with noxious stimuli in one conditioning context on learning and memory performance in a separate, non-aversively motivated task, juvenile recognition ability was examined in adult female rats exposed previously to one of two environmental stressors. In particular, experimental adult rats were either socially defeated by exposure to an aggressive conspecific rat or fear conditioned using single or multiple pairings with footshock prior to performance of the social recognition task. Experiment 1 established that repeated exposure to a single juvenile resulted in social memory formation reflected in decreased social investigation from the first to the second exposure. Experiment 2 documented that both single and multiple pairings of an environment with footshock produced robust freezing behavior (90–95% suppression of activity). In addition, fear conditioning produced a non-specific 5–60% increase in social investigation time in both single and multiple-pairing fear conditioned groups which confounded the ability of the social recognition measure to assess effects of fear conditioning on learning and memory performance per se. In contrast, Experiment 3 documented that when social recognition memory performance was impaired to 85% of control levels by imposition of a 2 h delay, exposure to a social defeat stressor reinstated optimal social recognition memory performance. These findings suggest that the after effects of fear conditioning include non-specific alteration of social investigation whereas exposure to conspecific aggression enhances subsequent social recognition memory.

Stress, social avoidance and anxiolytics: a potential model of stress-induced anxiety.

We investigated the social behavioural effects of a single exposure to either social defeat or electric shocks, using the recently developed social avoidance test in rats. The testing apparatus consisted of two connected chambers, one of which contained an unfamiliar male confined in a sub-chamber by a perforated Plexiglas wall. The subjects were placed in the empty chamber and, after 3 min of habituation, were allowed to explore the apparatus for 5 min. The latency, frequency and duration of visits made to the opponent-containing chamber were recorded. Both stressors reduced the exploration of the opponent-containing chamber for more than 5 days. The effects of electric shocks were not affected by housing conditions, whereas group housing protected rats from the long-term effects of defeat. In addition, the effects of social defeat in isolated rats lasted longer than the effects of electric shocks. These differences suggest that the two stressors have qualitatively different effects and may model different behavioural states in humans. In a second experiment, social avoidance induced by electric shocks was readily abolished by both chlordiazepoxide and buspirone. We suggest that the shock-induced social avoidance paradigm may become a useful model of stress-induced anxiety.

The Effects of Social Defeat and Other Stressors on the Expression of Circadian Rhythms

Most biological functions display a 24 u h rhythm that, in mammals, is under the control of an endogenous circadian oscillator located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The circadian system provides an optimal temporal organization for physiological processes and behavior in relation to a cyclic environment imposed upon organisms by the regular alternation of day and night. In line with its function as a clock that serves to maintain a stable phase-relationship between endogenous rhythms and the light-dark cycle, the circadian oscillator appears to be well protected against unpredictable stressful stimuli. Available data do not provide convincing evidence that stress is capable of perturbing the central circadian oscillator in the SCN. However, the shape and amplitude of a rhythm is not determined exclusively by the SCN and certain stressors can strongly affect the output of the clock and the expression of the rhythms. In particular, social stress in rodents has been found to cause severe disruptions of the body temperature, heart rate and locomotor activity rhythms, especially in animals that are subject to uncontrollable stress associated with defeat and subordination. Such rhythm disturbances may be due to effects of stress on sub-oscillators that are known to exist in many tissues, which are normally under the control of the SCN, or due to other effects of stress that mask the output of the circadian system. These disturbances of peripheral rhythms represent an imbalance between normally precisely orchestrated physiological and behavioral processes that may have severe consequence for the health and well being of the organism.

Effects of social defeat and of diazepam on behavior in a resident–intruder test in male DBA/2 mice

Social stress induces robust behavioral and physiological changes, some of which may alter the responsiveness to pharmacological agents, including diazepam (DZP). We used a resident–intruder paradigm to (1) develop a comprehensive ethogram of behavioral changes following social defeat (SD) in the socially reactive strain, DBA/2 male mice, (2) determine whether acute exposure of DBA/2 mice to low-dose DZP would induce flight or aggressive behavior, both of which have been observed in other rodent models and (3) to test whether prior social stress affects responses to DZP. Behavioral responses to a nonaggressive intruder (NAI) mouse 24 h post-SD were measured in resident subject mice exposed to DZP (0, 0.5, 2.0 mg/kg, ip) either prior to the resident–intruder test (Experiment 1) or immediately post-SD (Experiment 2); control mice were not defeated (NOSD). In general, SD mice displayed increased passive and active avoidance, defense, immobility, and risk assessment relative to NOSD mice. In Experiment 1, mice treated acutely with 0.5 mg/kg DZP had more approach and flight behavior, while those treated with 2.0 mg/kg DZP had more avoidance than vehicle-treated mice, independent of SD. In Experiment 2, acute DZP (2 mg/kg) induced effects 24 h later, possibly secondary to withdrawal. In a nonsocial context (Experiment 3), DZP increased exploratory activity.