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Opioid peptides and behavioral and physiological responses of dairy cows to social isolation in unfamiliar surroundings.

To test whether endogenous opioid peptides are involved in the behavioral and physiological responses of cattle to stress, 12 Holstein cows were either placed in social isolation in unfamiliar surroundings for 15 min or remained in their home stalls, either with or without naloxone treatment, following a Latin square design. Vocalizations (judged as high or low frequency), defecation/urination, and heart rate were recorded, latency to respond to local thermal stimulation of the leg by means of a laser was measured to detect pain sensitivity, and blood was sampled and assayed for cortisol concentrations. Naloxone in the home stall increased cortisol concentrations and tended to reduce response latencies to the laser but did not induce vocalization. Social isolation increased the incidence of high-frequency vocalization and of defecation/urination, heart rate, cortisol concentrations, and response latencies to the laser. Prior administration of naloxone increased the incidence of low-frequency vocalization in isolation, but it had no effect on heart rate or on responses to the laser and only limited effect on cortisol concentrations when the cows were isolated. Brief periods of social isolation in unfamiliar surroundings seem to be stressful to cows, as indicated by increased heart rate, hypothalamic-pituitary-adrenocortical axis activity, and vocalization. Isolation also reduces pain sensitivity, suggesting a stress-induced analgesia. However, we found no evidence that naloxone-sensitive opioid receptors were involved in these responses.

Animals↗

Deficits in exploratory behaviour in socially isolated rats are not accompanied by changes in cerebral cortical adrenoceptor binding.

Social isolation of rats produces marked deficits in exploratory behaviour in a novel environment. To test our hypothesis that adrenoceptors are modified by social isolation we have measured alpha 2- and beta-adrenoceptor binding in the cerebral cortex of rats isolated for 21 days starting immediately after weaning. After this period the animals showed a significant reduction in exploration in the elevated X-maze and increased avoidance of bright light in a two-compartment shuttlebox. There were no changes in adrenoceptor binding at this time, however. The implications of these findings are discussed.

Animals↗

Social isolation and loneliness: differences between older rural and urban Manitobans.

The purpose of this paper was to identify predictors of social isolation and loneliness for very old rural and urban adults. With data from the 1996 Aging in Manitoba Study (N = 1,868; age range 72-104), separate multiple regression models were constructed for rural and urban sub-samples, using the life space index (LSI) to measure social isolation as one outcome, and a loneliness index created by the authors from a combination of items to measure loneliness as a second outcome. Different factors were found to predict the outcomes for the two sub-samples. The models with isolation as the outcome produced five predictors for the rural sub-sample and three for the urban sub-sample. Only living alone was the same for both groups. The models with loneliness as the outcome produced five predictors for the rural sub-sample and two for the urban sub-sample, again with only one factor in common--four or more chronic illnesses. We conclude that health and social factors are important predictors of social isolation and loneliness, and sensitivity to these factors may improve the experience of older adults.

Aged↗

Majonoside-R2 reverses social isolation stress-induced decrease in pentobarbital sleep in mice: possible involvement of neuroactive steroids.

Majonoside-R2 (MR2) is a major ocotillol-type saponin constituent of Vietnamese ginseng. We investigated the effect of MR2 on the social isolation stress-induced decrease in pentobarbital sleep in mice, and elucidated the possible involvement of neurosteroidal sites of the GABA(A) receptor complex in the pharmacological activity of MR2. MR2 (3.1-6.2 mg/kg, i.p. or 5-10 microg, i.c.v.) dose-dependently reversed the decrease in pentobarbital sleep caused by social isolation stress to the level of sleep in the group-housed mice, but it had no effect on pentobarbital sleep in group-housed mice. Allotetrahydrodeoxycorticosterone (5alpha-pregnane-3alpha,21-diol-20-one, allo-THDOC; 12.5 microg, i.c.v.), the positive allosteric modulator of the GABA(A) receptor, and alpha-helical CRF(9-41) (alpha hCRF; 25 microg, i.c.v.), the corticotropin-releasing factor (CRF) antagonist, also reversed the decrease in pentobarbital sleep caused by social isolation stress. The reversing effects of i.c.v. MR2 and i.c.v. allo-THDOC on the decrease in pentobarbital sleep in isolated mice were significantly attenuated by pregnenolone sulfate (10 microg, i.c.v.), the steroidal negative allosteric modulator of the GABA(A) receptor. In contrast, when injected i.c.v., MR2, as well as allo-THDOC and alpha hCRF, significantly reversed the decrease in pentobarbital sleep induced by pregnenolone sulfate (10 microg, i.c.v.) and CRF (10 microg, i.c.v.) in group-housed mice. These results suggest that the reversing effect of MR2 on the social isolation stress-induced decrease in pentobarbital sleep is mediated by the neurosteroid site on the GABA(A) receptor complex in mice.

Animals↗

Early social isolation alters behavioral and physiological responses to an endotoxin challenge in piglets.

Psychosocial stress in the form of maternal deprivation and social isolation during early postnatal life induces persistent alterations in behavioral and physiological mechanisms of adaptation. One consequence may be an increased susceptibility to diseases in later life. Therefore, the aim of the present study was to investigate in domestic piglets the effects of a repeated social isolation (2 h daily from day 3 to day 11 of age) on behavioral, endocrine and immune responses to an endotoxin challenge with lipopolysaccharide (LPS) 1 day or 45 days after the isolation period. Peripheral LPS administration caused serious sickness behavior (somnolence, shivering, vomiting) and provoked profound increases in circulating tumor necrosis factor-alpha (TNF-alpha), ACTH and cortisol concentrations. The prior social isolation treatment enhanced signs of sickness and impaired suckling behavior. Early isolated piglets responded to LPS by an increase of shivering on day 12 and by increased vomiting on day 56 compared to controls. Further, there were considerable delays and reductions of time isolated piglets spent suckling on day 12. The repeated isolation stressor diminished TNF-alpha increases after LPS, whereas stress hormone levels were not significantly affected by isolation treatment. Finally, stronger relationships between signs of sickness and physiological measures were revealed in early isolated piglets. The duration of somnolence in isolated piglets was related to changes of cortisol and TNF-alpha concentrations, and the highest impact on duration of shivering was found for changes in cortisol and corticosteroid binding globulin levels. The present results suggest a sustained adaptive sensitization of coping with infection by social stress experience during early development in piglets.

Adrenocorticotropic Hormone↗

A critical period for social isolation in the rat.

Rats housed in social isolation show heightened levels of object-contact in an open-field and are slower than socially-housed controls to emerge from a small enclosure into an unfamiliar environment. Isolation between 25 and 45 days of age produced an irreversible effect upon object contact but had no lasting effect if between 16 and 25 days or after 45 days. In contrast to object contact, emergence was affected by isolation at any age and the effect was reversed by subsequent social housing. Thus the effects of isolation upon object contact and upon emergence apparently do not depend upon a single underlying variable.

Animals↗

Marital status, anomie, and forms of social isolation: a case of high suicide rate among the widowed in an urban sub-area.

This study examines the high suicide rate among the widowed in a census tract population in Flint, Michigan, and identifies the social psychological factors of anomie, actual social isolation, and future social isolation as etiologic factors in widow suicide. Explanations of widow suicide are discussed, and recommendations are made for the reduction of the suicide rate.

Age Factors↗

The effect of social isolation on androgen and corticosteroid levels in a cichlid fish (Haplochromis burtoni) and in swordtails (Xiphophorus helleri).

The blood androgen and glucocorticoid levels of male Haplochromis burtoni and Xiphophorus helleri were measured in socially isolated individuals (8 and 4 weeks, respectively) and nonisolated controls. In both species social isolation leads to significant reductions of mean concentrations and variances, both for androgens and corticosteroids. It is known for H. burtoni--and new evidence for X. helleri is presented--that social isolation reduces aggressivity in nonescalating situations. It is proposed that social stimuli in both species stimulate the testes to produce more androgenic hormones, and that this can lead to higher levels of aggression. At least in tropical fish species the androgenic optimum for defending a territory or a social status may be much more controlled by social stimuli than previously realized.

Adrenal Cortex Hormones↗

Involvement of TNF-alpha in enhancement of invasion and metastasis of colon 26-L5 carcinoma cells in mice by social isolation stress.

Psychosocial stress has been implicated in tumor metastasis. We have previously reported that social isolation stress exacerbated liver metastasis of colon 26-L5 by partially suppressing the cellular immunity in male Balb/c mice. To further understand the mechanism underlying the influence of isolation stress on liver metastasis, we investigated the effect of social isolation stress on tumor invasion, which is considered to be a pivotal step of tumor metastasis. The invasion and migration of tumor cells obtained from tumor nodules in the isolated mice were more markedly enhanced than that in the group-housed mice. The mRNA expression of proteolytic proteases, including matrix metalloproteinase (MMP)-2, MMP-9, membrane type 1 (MTI)-MMP, and urokinase-type plasminogen activator (u-PA), were increased in the tumor and liver tissues of the isolated mice compared with the control mice. On the other hand, production of plasma TNF-alpha and expression of hepatic TNF-alpha mRNA were elevated in the isolated mice with or without tumor burden. Increased TNF-alpha level was particularly discernible in the liver of tumor-bearing mice. Elevated positive staining for TNF-alpha was immunohistochemically observed within and around tumor mass in the liver from isolated tumor-bearing mice, compared with group-housed mice. In addition, the invasiveness of tumor cells and the expression of proteolytic enzymes, including MMP-9 and u-PA in tumor cells, were enhanced by the treatment of TNF-alpha in vitro. Thus, the data suggested that isolation stress-augmented TNF-alpha may be involved in the enhancement of tumor invasion and metastasis in part by upregulating the proteolytic enzymes such as MMPs and u-PA in tumor and liver tissues.

Animals↗

An experimental study of social isolation of elderly people: psychoendocrine and metabolic effects.

Psychoendocrine and metabolic effects of social isolation and understimulation in real life were examined in a controlled study of 60 elderly people representative of their age group. Together with the staff and the elderly, a social activation program was formed at a senior citizen apartment building. Half of the elderly were part of this activation program (experimental group). The other half constituted the control group. Blood sampling and psychosocial testing were performed immediately before and after 3 and 6 months of social activation. Social activation increased threefold in the experimental group. Height decreased in the control group compared to the experimental subjects. Plasma levels of testosterone, dehydroepiandrosterone, and estradiol increased significantly in the experimental group over the 6-month period compared to the control group. The most pronounced increase took place during the initial 3 months. Hemoglobin A1c decreased significantly in the experimental group over the 6-month period compared to the control group. In this preliminary study it is concluded that social isolation and understimulation may be associated with a wide range of psychophysiologic effects in elderly people.

Aged↗

Social isolation increases cholecystokinin mRNA in the central nervous system of rats.

To investigate cholecystokinin (CCK) mRNA changes induced by social isolation rats were isolated in single cages soon after weaning for 30 days. They were then sacrificed and their brains removed for in situ hybridization (ISH) study. Control animals were housed in groups of 6 per cage for the same period. ISH was performed using a 32P-labelled oligonucleotide probe complementary to CCK-8 mRNA and the results analysed by computerized densitometry. They showed a significant increase (from 59.5-152.3%) in CCK mRNA expression in the basolateral amygdala, cortex, CA1, dorsal raphe nucleus, geniculate body and ventral tegmental area of isolated rats. These results suggest that social isolation may influence CCK gene expression.

Animals↗

Socially isolated children 20 years later: risk of cardiovascular disease.

OBJECTIVE: To test the hypothesis that children who occupy peripheral or isolated roles in their peer groups (isolated children) are at risk of poor adult health. DESIGN: Longitudinal study of an entire birth cohort. SETTING: Dunedin, New Zealand. PARTICIPANTS: A total of 1037 children who were followed up from birth to age 26 years. INTERVENTIONS: Measurement of social isolation in childhood, adolescence, and adulthood. MAIN OUTCOME MEASURES: When study members were 26 years old, we measured adult cardiovascular multifactorial risk status (overweight, elevated blood pressure, elevated total cholesterol level, low high-density lipoprotein level, elevated glycated hemoglobin concentration, and low maximum oxygen consumption). RESULTS: Socially isolated children were at significant risk of poor adult health compared with nonisolated children (risk ratio, 1.37; 95% confidence interval, 1.17-1.61). This association was independent of other well-established childhood risk factors for poor adult health (low childhood socioeconomic status, low childhood IQ, childhood overweight), was not accounted for by health-damaging behaviors (lack of exercise, smoking, alcohol misuse), and was not attributable to greater exposure to stressful life events. In addition, longitudinal findings showed that chronic social isolation across multiple developmental periods had a cumulative, dose-response relationship to poor adult health (risk ratio, 2.58; 95% confidence interval, 1.46-4.56). CONCLUSIONS: Longitudinal findings about children followed up to adulthood suggest that social isolation has persistent and cumulative detrimental effects on adult health. The findings underscore the usefulness of a life-course approach to health research, by focusing attention on the effect of the timing of psychosocial risk factors in relation to adult health.

Adolescent↗

Effect of the GABA-transaminase inhibitor vigabatrin on exploratory behaviour in socially isolated rats.

Elevation of the brain levels of the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by inhibiting the GABA-catabolizing enzyme GABA-transaminase (GABA-T) is known to induce a number of functional effects including changes in behaviour. Vigabatrin (gamma-vinyl GABA, GVG) is an anti-epileptic drug that increases brain GABA levels by an irreversible inhibition of GABA-T. Using the elevated plus-maze model of anxiety and the open-field behaviour test, the effects of GABA-T inhibition and social isolation on rat exploratory behaviour were investigated. Social isolation for 1 week did not induce any change in the exploratory-behaviour of adult rats. However, rats socially isolated for 2 weeks, showed suppressed exploratory behaviour in the elevated plus-maze test. In both groups of differentially housed rats, treatment with vigabatrin at a dose of 250 mg/kg, i.p., significantly reduced the anxiety level in the plus-maze test. In the open-field test, vigabatrin tended to increase the exploratory behaviour only in the group of isolated rats. The results may suggest that vigabatrin has a better anxiolytic-like effect in the isolated rats than that in the socially housed rats.

4-Aminobutyrate Transaminase↗

The influence of social isolation and peripheral innervation on Ehrlich tumor growth in mice.

The relationship between social isolation and Ehrlich tumor growth was investigated in seven male NIH mice about 2 months old living separately in small cages for 28 days. Fifteen control animals were kept grouped in conventional cages (10 animals in one and 5 in another) for the same period. After this period, 40 to 50 microliters of a cell tumor suspension at a concentration of 1 to 5 x 10(7) tumor cells/ml was inoculated into the footpad and footpad size was measured for 10 days. Isolated mice presented a 30% reduction in tumor growth. Sciatic and saphenous neurectomy in one leg of 5 isolated mice (experimental) and 5 grouped mice (control) performed 7 days before tumor inoculation abolished this difference, and more tumor growth was observed in the neurectomized paw compared to the non-neurectomized paw. The subordinate x dominant social relationship established between mice living in groups of two per cage (seven cages) did not modify the growth of tumor inoculated under the same conditions compared to the first experiment. We conclude that social isolation and an intact peripheral innervation are associated with reduced tumor growth, but dominance behavior has no effect.

Analysis of Variance↗

Effects of early weaning and social isolation on the expression of glucocorticoid and mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase 1 and 2 mRNAs in the frontal cortex and hippocampus of piglets.

Pigs weaned at young ages show more abnormal and aggressive behaviors and cognitive deficits compared to later weaned pigs. We investigated the effects of age, weaning and/or social isolation on the expression of genes regulating glucocorticoid response [glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11beta-hydroxysteroid dehydrogenases 1 and 2 (11beta-HSD1 and 11beta-HSD2)] in the frontal cortex and hippocampus. Early- (EW; n = 6) and conventionally-weaned (CW; n = 6) piglets were weaned at 10 and 21 days after birth, respectively. Non-weaned (NW) piglets of both ages (NW; n = 6/group) remained with their dams. Immediately before euthanasia, half of CW, EW and NW animals were socially isolated for 15 min at 12 (EW, NW) and 23 (CW, NW) days of age. Differences in amounts of 11beta-HSD1, 11beta-HSD2, GR and MR mRNA were determined by quantitative real-time RT-PCR and data subjected to multivariate linear mixed model analysis. When compared with NW piglets at 12 days of age, the hippocampi of EW piglets showed decreased gene expression (P < 0.01). Social isolation decreased gene expression (P < 0.05) in the frontal cortex of all piglets. Twelve-day-old piglets showed higher MR mRNA in the frontal cortex (P < 0.01) and lower 11beta-HSD2 and GR mRNA (P < 0.05) in the hippocampus compared to 23-day-old animals. Results indicate that EW affected the hippocampus of piglets at 12 days of age, while social isolation affected frontal cortex regardless of age. These results may be correlated with behavioral and cognitive changes reported in EW piglets.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

Social isolation increases aggressive behaviour and alters the effects of diazepam in the rat social interaction test.

Isolation rearing in the early stages of life has been shown to modify a variety of behaviours in many animals and the responsitivity to psychotropic drugs. The aims of the present study were to investigate the effects of isolation rearing on anxiety using the social interaction paradigm and to compare the effects of diazepam on social interaction behaviours in isolation and socially reared rats. Male Lister hooded rats were reared from weaning either alone (isolation reared) or in groups of four (socially reared) for 6 weeks and then were tested for social interaction. Both isolation and socially reared rats were exposed to the social interaction test either without drug treatment or following saline or diazepam (1 and 2.5 mg/kg, i.p., 30 min before testing). The results demonstrate that under high light in an unfamiliar arena, the isolation compared to the socially reared rats showed a significantly (P < 0.01) higher level of social interaction, manifested as increases in aggressive and avoidance behaviours, and that this interaction occur for a greater length of time during the test period (10 min). However, when the light level was decreased or when the arena was familiar, active social interaction of isolation reared rats decreased but increased in the socially reared rats. In both conditions the isolation reared rats displayed more aggressive behaviours, in particular biting and boxing the partners which did not occur with the socially reared rats. Pretreatment of diazepam (1 and 2.5 mg/kg., i.p.) caused a dose-related reduction in aggressive behaviours in rats reared under both conditions but increased passive interactions in the socially reared rats. In contrast diazepam (2.5 mg/kg) reduced active interaction in the isolation reared rats but had no effect on passive interaction. These results indicate that isolation rearing increases aggressive behaviours and alters the effects of diazepam.

Aggression↗

Decreased access to health care and social isolation among young adults with cerebral palsy after leaving school.

OBJECTIVE: To examine if leaving special schools has a negative impact on the health care and social isolation of young adults with cerebral palsy. METHODS: Young adults with cerebral palsy, aged between 15 and 22 years, were divided into 2 cohorts: current students, who were still receiving services from special schools, and school-leavers, who had since been discharged from care. A questionnaire and physical examination were administered to assess the extent of disability, health care received by, and social isolation of these young adults. RESULTS: School-leavers had a greater degree of dissability than did students, although the results were not statistically significant. Health care exposure to specialists, general practitioners, therapists physiotherapists, occupational therapists, and/or speech therapists), and medical social workers decreased after leaving school; with the exception of contact with general practitioners, these results were significant (p<0.05). The entire cohort was more socially isolated than a control cohort. School-leavers participated in fewer activities outside their homes, but showed less concern about their disability than did current students. CONCLUSIONS: Young adults with cerebral palsy continue to have health care and lifestyle needs after leaving school, which are currently not being adequately met.

Adolescent↗

Relationship of depression, anxiety, and social isolation to chronic heart failure outpatient mortality.

OBJECTIVES: The Psychosocial Factors Outcome Study (PFOS) investigated the prevalence of depression and anxiety and the relationship of psychosocial factors to mortality in outpatients with heart failure (HF). BACKGROUND: Considerable evidence links psychosocial factors to coronary heart disease mortality and sudden cardiac death (SCD). The contribution of psychosocial factors independent of disease severity to HF outpatient mortality is not well elucidated. METHODS: Patients (N = 153) from 20 Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) sites participated in the PFOS. SCD-HeFT provided demographic, medical history, and cardiac data. Participants completed questionnaires to assess psychosocial status at PFOS entry. RESULTS: Depression and anxiety were common in HF outpatients (36% Beck Depression Inventory-II > or = 13; 45% State Trait Anxiety Inventory > or = 40). Depression, anxiety, and social support amount did not differ in the SCD-HeFT treatment groups: implantable cardioverter defibrillator, amiodarone, and placebo medication. Fifteen (9.8%) patients died during mean follow-up at 23.6 months (SD = 8.2). In Cox regression controlling for treatment, depression, anxiety, and social isolation separately predicted mortality; perceived HF-specific functional status did not. Depression (ln) [P = .04, hazard ratio (HR) = 1.81] and social isolation (P = .04, HR = 2.25), but not anxiety, predicted mortality independent of demographics, clinical predictors, and treatment. When simultaneously including significant demographic, clinical, and psychosocial predictors and treatment groups, depression (ln) (P = .022, HR = 2.2) and social isolation (P = .094, HR = 1.75) predicted mortality. All-cause mortality was 12% for depressed patients and 9% for others. CONCLUSION: This study finds a high prevalence of anxiety and confirms the high prevalence of depression in the HF outpatient population. Depression and social isolation predicted mortality independent of demographic and clinical status in HF outpatients.

Adult↗