A single social defeat induces short-lasting behavioral sensitization to amphetamine

Repeated, intermittent exposure to psychostimulants or stressors results in long-lasting, progressive sensitization of the behavioral effects of a subsequent amphetamine (AMPH) challenge. Although behavioral sensitization has also been observed following a single drug pretreatment, the sensitizing potential of a single exposure to stress is not clear. Both drug- and stress-induced sensitization depend on an enhanced dopaminergic neurotransmission in the mesolimbic DA system. Apart from responding to rewards, this system is also involved in responding towards aversive social stimuli. Therefore, social stressors may be particularly effective in inducing cross-sensitization to stimulant drugs. We examined the time course of sensitization to the locomotor effects of the stimulant, AMPH, following a single social stressor: a social defeat. Wistar rats were exposed in a resident-intruder paradigm to an unfamiliar dominant male conspecific (Wild-Type Groningen), resulting in defeat. The locomotor effects of a subsequent AMPH challenge (0.25 or 1.0 mg/kg) were evaluated 3, 14, and 21 days later by scoring horizontal movement in an open field. AMPH had significantly larger locomotor-activating effects in animals that had been defeated 3 days earlier compared to nondefeated controls. However, this sensitized response was no longer present 14 or 21 days after defeat. Therefore, we conclude that social defeat induces short-lasting cross-sensitization to the locomotor effects of AMPH in rats, but is not sufficient for long-term sensitization. The transient enhancement of responses to dopaminergic drugs may be indicative of a temporary role of dopamine in the cascade of physiological and behavioral changes following social defeat.     

Pair housing affects anxiety-like behaviors induced by a social but not by a physiological stressor in male Swiss mice

The role of pair housing in the modulation of anxiety-like behaviour in socially and physiologically stressed mice was investigated. The protocol of psychosocial stress consisted of submitting male adult mice to daily social confrontation with a male conspecific for a period of thirteen days. In an attempt to study a possible effect of pair housing as a social support, each male mouse was housed with a female throughout the period of experimentation, except during the agonistic interactions. As a physiological stressor, 10(9) sheep red blood cells (SRBC)/ml were injected intraperitoneally on the 1st and 7th days of the experiments. The respective control groups were as follows: non-socially stressed, non-pair housed and saline-injected mice. The humoral immune response was analysed by haemagglutination assay. The level of anxiety-like behaviours was measured in the elevated plus-maze test on the 13th day of the experiment. As a result, no significant changes in humoral immunity to SRBC were observed in mice subjected to social confrontation in a neutral arena as compared to non-socially stressed mice. As a consequence, no effect of pair housing on humoral immunity to SRBC could be evaluated. Concerning the effects of pair housing on the anxiety-like behaviours, it was possible to demonstrate that the pair housing proved to be effective in modulating anxiety-like behaviour, although in the stressed groups the percentage of time in the open arms and the time in risk assessment did not change in a symmetrical opposite form, as expected. The physiological stressor induced an anxiety-like behaviour that was not reversed by the pair housed condition. This suggests that different types of stressors activate different neural and peripheral pathways, which may or may not be modulated by pair housing, a finding that deserves our attention as a way to better understand the mechanisms that influence adaptations to stress.     

Sequential analysis of juvenile isolation-induced decreased social behavior in the adult rat.

The consequences of juvenile isolation on adult social behavior were studied in detail using two different analysis methods: frequency, duration, and latency of behavioral elements, and sequential analysis. Rats were either isolated or socially housed during weeks 4 and 5 of age, and after the isolation period housed in pairs with a rat of identical housing condition until the time of testing at 12 weeks of age. Juvenile isolation caused marked effects on the frequency, duration, and latency of various social behavioral elements, whereas the non-social activities such as ambulation, rearing, and self-grooming were hardly affected. Juvenile isolation reduced social exploration, anogenital sniffing, and approach/following and increased the latency to the first occurrence of these social behavioral elements. In contrast, the sequential analysis revealed that the structure of social behavior was barely affected by juvenile isolation. Some transitions were less pronounced in juvenile isolated rats compared to non-isolated rats, but no significant differences were observed in transitions between social elements. Thus, juvenile isolation bisected the time spent on adult social interactions, whereas it did not disrupt the sequential structure of social behavior. The present data suggest that juvenile isolation reduced the motivation for adult social behavior, but when social contact is initiated, a relatively normal social behavioral pattern is displayed.     

Stress-dependent changes in neuroinflammatory markers observed after common laboratory stressors are not seen following acute social defeat of the Sprague Dawley rat

Exposure to acute stress has been shown to increase the expression of pro-inflammatory cytokines in brain, blood and peripheral organs. However, the nature of the inflammatory response evoked by acute stress varies depending on the stressor used and species examined. The goal of the following series of studies was to characterize the consequences of social defeat in the Sprague Dawley (SD) rat using three different social defeat paradigms. In Experiments 1 and 2, adult male SD rats were exposed to a typical acute resident-intruder paradigm of social defeat (60 min) by placement into the home cage of a larger, aggressive Long Evans rat and brain tissue was collected at multiple time points for analysis of IL-1β protein and gene expression changes in the PVN, BNST and adrenal glands. In subsequent experiments, rats were exposed to once daily social defeat for 7 or 21 days (Experiment 3) or housed continuously with an aggressive partner (separated by a partition) for 7 days (Experiment 4) to assess the impact of chronic social stress on inflammatory measures. Despite the fact that social defeat produced a comparable corticosterone response as other stressors (restraint, forced swim and footshock; Experiment 5), acute social defeat did not affect inflammatory measures. A small but reliable increase in IL-1 gene expression was observed immediately after the 7th exposure to social defeat, while other inflammatory measures were unaffected. In contrast, restraint, forced swim and footshock all significantly increased IL-1 gene expression in the PVN; other inflammatory factors (IL-6, cox-2) were unaffected in this structure. These findings provide a comprehensive evaluation of stress-dependent inflammatory changes in the SD rat, raising intriguing questions regarding the features of the stress challenge that may be predictive of stress-dependent neuroinflammation.     

Aging-related changes in the effects of social isolation on social behavior in rats

Aging is generally associated with cognitive dysfunction and alterations in emotional response. Moreover, in social situations, aging decreases social interaction with unfamiliar individuals, suggesting the decline of social cognition/motivation and a high level of anxiety. Although it is known that isolation housing has various effects on subsequent behavior, including social interaction depending on the age at isolation, the effects of isolation on aged subjects have not been examined. In the present study, we investigated the effects of aging and different periods of isolation housing on social interaction in male F344/N rats. Young (3-4 months old) and aged (24-25 months old) rats were either group-housed or socially isolated for 2 or 4 weeks. The rats were tested with age-matched and group-housed unfamiliar males in a social interaction test, and social (e.g. approach/following and sniffing) and non-social behaviors (e.g. self-grooming and ambulation) were recorded. The results indicated that group-housed aged rats showed less approach/following, sniffing, and ambulation than group-housed young rats. Moreover, in young rats, isolation housing gradually increased approach/following and sniffing depending on the isolation period. In contrast, in aged rats, more prolonged isolation (4 weeks) attenuated the 2-week isolation-induced increase of sniffing behavior and had no effect on approach/following. The present study suggests that aging decreases social investigation and induces high emotional response to a novel social environment, and that the behaviors can be differentially affected by social isolation depending on the age at isolation and the period of isolation.     

Pair housing induced feeding suppression: individual housing not novelty

Male rats that are moved from individual to pair housing suppress their feeding for a few days [O'Connor R, Eikelboom R. The effects of changes in housing on feeding and wheel running. Physiol Behav 2000;68:361-371]. The present study explored whether the suppression was a result of the period of individual housing or the novelty of the other animal. Two groups of 16 rats were pair-housed and one group of rats was individually housed for 21 days. The individually housed rats were then pair-housed (IP group) and rats in one of the pair-housed groups were re-housed with novel partners (NP group), while rats in the other pair-housed group remained with the same partner (SP group). Feeding was suppressed only for rats in the IP group, suggesting that the novelty of the partner did not suppress feeding, but rather, the change from individual to pair housing did. Water consumption was also measured, but was unaffected by the re-housing manipulation.     

Individual housing does not influence the adaptation of the pituitary-adrenal axis and other physiological variables to chronic stress in adult male rats

Although the influence of housing conditions on the physiological response to stress has been extensively studied for several years, no attempts have been made to investigate the effect of this variable on the capacity for adaptation to chronic stress. To this end, adult male rats were housed either individually or in groups of four per cage and subjected to 2 hr of daily immobilization stress for 14 days. Housing did not influence any of the physiological variables measured either in unstressed or in stressed rats except the corticosterone response to stress which was higher in individually housed rats. Of the behavioral measures, individual housing significantly decreased defecation rate in the novel environment. Other behavioral measures were not influenced by housing. Chronic stress significantly reduced ambulation but no significant interaction between housing and chronic stress was observed. Taken together, these data indicate that a short period of individual housing did not affect the physiological and behavioral consequences of repeated exposure to chronic stress.     

Alcohol intake in social housing and in isolation before puberty and its effects on voluntary alcohol consumption in adulthood

We assessed the effects of alcohol exposure in social and isolation housing before puberty on the alcohol consumption later in adulthood. From 25 to 35 days of age, Wistar male rats were exposed to either (a) continuous isolation; (b) continuous social housing; (c) continuous isolation, but placed in social housing during 12 hr every other day; or (d) continuous social housing, but placed in isolation during 12 hr every other day (SOIS group). All males were exposed to 8% ethanol as the only available liquid 12 hr/day every other day in this prepubescent period and to continuous free-choice access to 8% ethanol or water in both social and isolation housing when adulthood was reached. Alcohol consumption before puberty was higher in the group permanently housed in isolation. Both voluntary alcohol intake and preference for alcohol in adulthood also were higher during the isolation than in the social condition in all groups, except in the SOIS group. Alcohol consumption was higher in the SOIS group than in the other groups only during social condition in adulthood. Food intake decreased during the social interaction of the groups that changed their condition from isolated to social or from social to isolated. Results support that (a) isolation facilitates alcohol consumption, and (b) rearing characteristics associated to alcohol intake at an early age can play an important role in later alcohol intake.     

Modulation of the pair housing induced feeding suppression

The present experiments explored how manipulating the period of individual housing, partner novelty, or short periods of conspecific interaction affected the feeding suppression evident when young adult male rats were moved from individual to pair housing. In the first experiment, after a period of pair housing, rats were individually housed for 0, 3, 10, or 14 days before being rehoused with either the same or a novel partner. There was an increase in the feeding suppression as the duration of individual housing grew, and at 3 days, the novel partner produced a stronger suppression than did the familiar partner. In the second experiment, four 15-min exposures to a conspecific in a novel place preference environment did not eliminate the feeding suppression at pair housing. The third experiment found that four 90-min exposures to a conspecific reduced the feeding suppression evident at rehousing. In Experiments 2 and 3, an environment previously paired with a conspecific did not produce a place aversion. Together, these experiments suggest that the feeding suppression evident when male rats are moved from individual to pair housing can be considered a graded effect open to modulation by a variety of behavioral manipulations.     

Opioid activity in behavioral and heart rate responses of tethered pigs to acute stress

In a longitudinal experiment, effects of long-term tether housing on heart rate and behavioral responses to an acute stressor (a 15-min challenge with a nosesling) were investigated in pigs. The animals were challenged during loose housing and again after 10-11 weeks of tether housing. To detect possible changes in endogenous opioid systems modifying these responses, the pigs were pretreated with the opioid receptor antagonist naloxone (0.5 mg/kg body weight, iv). In response to the nosesling challenge, the animals showed pronounced resistance behavior and a sharp rise in heart rate. Following this initial phase of resistance, the heart rate dropped to prechallenge levels or below this line, and the pigs seemed to become sedated. Pretreatment with naloxone increased the heart rate response in animals that were long-term tether housed (n=12). No such effect was found in the control group (n=5) that was loose-housed during the entire experiment, indicating that the impact of endogenous opioid systems mitigating heart rate responses to acute stress had increased as a result of long-term tether housing. Changes in the effect of naloxone on the behavioral response were not found. Adaptive changes in opioid systems may prevent excessive physiological reactions to acute stress and, thus, may serve as a coping mechanism.     

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.     

Preoperative differential housing and dorsal hippocampal lesions in rats

Rats housed in impoverished environments often show greater behavioral deficits after receiving brain lesions than to rats housed in standard or enriched environments. However, the resemblance between the effects of social isolation and those of hippocampal lesions in rats prompted the suggestion that rats socially isolated at weaning rather than grouped counterparts may show less behavioral change after sustaining dorsal hippocampal lesions when adult. In socially reared rats, hippocampal lesions produced increased ambulation and object contact in an open field, reduced passive avoidance in a runway task, and produced faster acquisition of active avoidance in a shuttle box, but there were no such differences in isolation-reared rats. Ambulation and object contact in isolates were intermediate to those of rats with lesions and intact group-housed rats, and the behavior of isolates during passive and active avoidance training was generally similar to that of grouped rats with lesions. The introduction of a distractor during approach training in an alley reduced running speeds more in rats with lesions than in controls. The several significant interactions between housing state and lesion state suggest that neural pathways associated with the hippocampal formation may mediate some behavioral effects of differential housing.     

Effects of single and group housing conditions and alterations in social and physical contexts on amphetamine-induced behavioral sensitization in rats

Repeated administration of amphetamine (AMPH) can produce behavioral sensitization. However, whether contextual elements and housing conditions influence AMPH-induced behavioral sensitization remains uncertain. This study was designed to examine the effects of housing conditions (single- vs. group-housed) and different contextual changes, including social (with two other co-drug partners) and physical (novel box) context changes, on AMPH-induced behavioral sensitization. During the training phase, all rats were exposed for 7 days to AMPH (1 mg/kg, intraperitoneally) in a Locometer chamber, with the exception of animals tested for the effects of physical context changes trained in a novel box. Following a 7-day withdrawal phase, all rats received an AMPH (0.5 mg/kg) challenge, and locomotor activity in a Locometer box was recorded before and after AMPH injection during the testing phase. Under group housing conditions, animals exposed to a different physical environment between the training and testing phases or accompanying co-drug partners during the training phase exhibited decreased AMPH-induced locomotor sensitization. In contrast, single housing conditions did not have an inhibitory effect on AMPH-induced behavioral sensitization after manipulations of the physical and social contexts. These results suggest that under group housing conditions, both physical and social context changes can attenuate AMPH-induced behavioral sensitization. The possible neural mechanisms underlying the involvement of different housing conditions in AMPH-induced behavioral sensitization are discussed.     

The genetic liability to stress and postweaning isolation have a competitive influence on behavioral organization in rats

Rats housed in social isolation postweaning (isolates) show profound behavioral and neurobiological differences when compared to socially housed rats (socials). Fischer rats (F344) relative to Lewis rats are hyperresponsive and significantly more susceptible to stressful stimuli. This investigation tested the hypothesis that the behavioral effects of postweaning isolation are more pronounced in a strain of rats with high susceptibility to stress compared to a strain with low susceptibility to stress. Seventy male Sprague-Dawley, Lewis, and F344 rats were housed individually or in groups at weaning on Day 21 and tested on Day 85 in the Behavioral Pattern Monitor. There was no interaction between strain and postweaning isolation for measures of locomotor activity and exploratory behavior (holepoking). However, the postweaning isolation-induced increase in the frequency of repetitive straight movements, a measure of behavioral organization, was more pronounced in Lewis isolates compared to Sprague-Dawley and F344 isolates. These results do not support the hypothesis that rats with a higher susceptibility to stress show more pronounced changes in behavior following postweaning isolation; instead, increased susceptibility to stress may counteract the repetitive movement patterns induced by social isolation.     

Juvenile stress impairs body temperature regulation and augments anticipatory stress-induced hyperthermia responses in rats

Clinical studies have implicated adolescence as an important and vulnerable period during which traumatic experiences can predispose individuals to anxiety and mood disorders. As such, a stress model in juvenile rats (age 27-29 d) was previously developed to investigate the long-term effects of stress exposure during adolescence on behavior and physiology. This paradigm involves exposing rats to different stressors on consecutive days over a 3-day period. Here, we studied the effects of juvenile stress on long-term core body temperature regulation and acute stress-induced hyperthermia (SIH) responses using telemetry. We found no differences between control and juvenile stress rats in anxiety-related behavior on the elevated plus maze, which we attribute to stress associated with surgical implantation of telemetry devices. This highlights the severe impact of surgical stress on the results of subsequent behavioral measurements. Nonetheless, juvenile stress disrupted the circadian rhythmicity of body temperature and decreased circadian amplitude. It also induced chronic hypothermia during the dark phase of the day, when rats are most active. When subjected to acute social defeat stress as adults, juvenile stress had no impact on the SIH response relative to controls. However, 24 h later, juvenile stress rats displayed an elevated SIH response in anticipation of social defeat when re-exposed to the social defeat environment. Taken together, our findings indicate that juvenile stress can induce long-term alterations in body temperature regulation and heighten the increase in temperature associated with anticipation of social defeat. The outcomes of behavioral measurements in these experiments, however, are severely affected by surgical stress.     

Brief periods of positive peer interactions mitigate the effects of total social isolation in young Octodon degus

We investigated whether positive daily peer‐interactions counteract the effects of isolation in Octodon degus. Twenty‐five‐day‐old degus were either isolated (ISO), socially housed (SOCIAL), or isolated and allowed 1‐hr daily peer interaction (PARTIAL‐ISO). The animals were observed over 4 weeks. Just prior to isolation and after 2 weeks of individual housing, the subjects were assessed for response to pleasant stimuli via a sucrose preference test and to fearful situations in open field and startle tests. Two weeks after the previous tests, the subjects were retested as above and observed in novelty and sociability tests. Only the ISO group showed significant alterations in sensitivity to reward and increased risk‐taking behavior in fearful situations. The ISO group consumed more sucrose, spent less time freezing in the startle test and exhibited increased exploration in open field and novelty tests compared to PARTIAL‐ISO and SOCIAL groups. In the sociability test, the SOCIAL group vocalized more than the other two groups during encounters with an unfamiliar degus. Our findings suggest that (i) chronic isolation induces alteration of hedonic, emotional and social profiles, with a maturational delay in fear‐related responses; (ii) friendly interaction attenuates most behavioral changes induced by total social isolation. However, the positive effects of daily social interactions did not fully counteract deficits in social vocalizations. Our study represents one of the few available studies focused not only on the consequences of negative life events in this species, but also the protective role of relatively short periods of positive social activity on subsequent emotional development. © 2010 Wiley Periodicals, Inc. Dev Psychobiol 53:280–290, 2011.     

Facilitation of lordosis behavior in rats by social isolation: Adrenal mediation

Ovariectomized rats were housed either singly or in groups of three, with housing density kept constant. Subcutaneous injections of 0.8 μg estradiol benzoate (EB) were administered daily, beginning 6 days after surgery. The first two experiments provided evidence that isolation facilitated lordosis within 3 days of initial EB administration. Other behavioral components of female sexual receptivity were not affected. The third experiment involved comparison of the effects of isolation in ovariectomized and adrenalectomized-ovariectomized rats. Isolation again significantly facilitated lordosis in ovariectomized rats but no such trend was apparent in adrenalectomized rats even though high levels of lordosis were evident in these animals. One possible interpretation of this latter finding is that isolation of female rats facilitates estrogen-induced lordosis by increasing adrenocortical secretion. The present series of experiments demonstrate that social isolation can influence sexual receptivity in rodents.     

Social defeat differentially affects immune responses in Siberian hamsters (Phodopus sungorus)

Social defeat is a complex, multi-faceted behavioral interaction capable of eliciting a wide range of physiological and behavioral responses. The behavioral components responsible for eliciting these changes, however, remain unspecified. The goal of the present study was to examine the effects of chronic social defeat on serum cortisol concentration as well as innate and acquired immune responses in adult male Siberian hamsters (Phodopus sungorus). Specifically, we experimentally manipulated the nature of the social interaction among conspecific animals (i.e., no social interaction, exposure to the sight or smell of a conspecific, or full social defeat) in order to determine the important components contributing to potential stress-induced changes in immunity. We found that immunoglobulin G (IgG) levels were decreased in defeated animals relative to both control animals and those exposed only to the olfactory cues of conspecifics. In contrast, serum bactericidal activity was increased in the defeated animals relative to controls. Prolonged social defeat did not elevate serum cortisol levels as compared with control animals. The results of this study suggest that social defeat alters immune responses and that specific behavioral components (i.e., defeat) contribute to this response. Importantly, these findings also demonstrate that social defeat exerts opposite effects on innate and acquired measures of immunity. Collectively, these results contribute to our understanding of complex social behaviors and their differential effects on endocrine and immune responses in vertebrates.     

The effects of individual housing on 'anxious' behaviour in male and female gerbils

Gerbils are social animals and live in family groups in the wild, suggesting that individual housing may be a psychosocial stressor in this species. In the present study, gerbils were housed in same sex groups for 4 weeks, and then were either individually housed or remained with their cage mates for 1 week. Gerbils were tested in the black/white box (BWB), elevated plus maze (EPM) and social interaction test. Results indicated no significant differences in behaviour in the BWB. In contrast, on the EPM individually housed males showed increased anxiety compared to other groups, whilst there were no specific effects in females. In the social interaction test, however, individual housing in males increased social investigation, whilst females showed a decrease in exploration, accompanied by increased immobility. Passive immobility (freezing) was also increased in both sexes following individual housing. Thus, data from the EPM suggest that individual housing leads to increased anxiety mainly in males, whilst data from the SI suggests broadly the opposite. Therefore, individual housing results in different behavioural changes in male and female gerbils, which are dependent upon the test situation. This study highlights two key points. Firstly, it is important to use our knowledge of the species natural ecology in interpreting and designing anxiety tests. Secondly, it is important to assess behaviour in a range of situations when attempting to measure 'anxiety', particularly where tests developed for use in one species/sex are being used in another.     

Stress-induced social avoidance: a new model of stress-induced anxiety?

We have studied the long-term behavioral effects of a single stressor in male rats by using an approach/avoidance situation as the behavioral endpoint. A single exposure to social defeat or electric shocks was used as stressors. Behavioral testing was performed in a two-compartment cage divided by an opaque wall and connected by a short tunnel. The larger compartment contained an unfamiliar male rat that was separated from the rest of the compartment by a transparent, perforated Plexiglas wall. The subject was placed in the small compartment and allowed to explore the cage for 5 min. The test was performed on Days 1, 5, or 10 after stress application. Unstressed rats spent 90% of time in the large compartment that contained the unfamiliar male. Social defeat dramatically reduced the exploration of the large compartment, without time-related changes in this response. A mild electric shock had a similar effect that lasted more than 5 days but less than 10 days. The exploration of an empty cage was significantly less inhibited by stress than the exploration of a cage that contained the stimulus rat. The test could be applied repeatedly in the same rat, without major changes in the response. Chlordiazepoxide applied 1 h before behavioral testing abolished completely the stress-induced behavioral deficit. We suggest that the model can be used for studying the effects of various compounds on stress-induced anxiety.