Elsevier

Psychoneuroendocrinology

Volume 34, Issue 10, November 2009, Pages 1542-1553
Psychoneuroendocrinology

Oxytocin protects against negative behavioral and autonomic consequences of long-term social isolation

https://doi.org/10.1016/j.psyneuen.2009.05.017Get rights and content

Summary

Positive social interactions and social support may protect against various forms of mental and physical illness, although the mechanisms for these effects are not well identified. The socially monogamous prairie vole, which – like humans – forms social bonds and displays high levels of parasympathetic activity, has provided a useful model for investigating neurobiological systems that mediate the consequences of sociality. In the present study, adult female prairie voles were exposed to social isolation or continued pairing with a female sibling (control conditions) for 4 weeks. During weeks 3 and 4 of this period, animals were administered oxytocin (20 μg/50 μl, SC) or saline vehicle (50 μl, SC) daily for a total of 14 days. In Experiment 1, autonomic parameters were recorded during and following isolation or pairing. Isolation (vs. pairing) significantly increased basal heart rate (HR) and reduced HR variability and vagal regulation of the heart; these changes in isolated animals were prevented with oxytocin administration. In Experiment 2, behaviors relevant to depression [sucrose intake and swimming in the forced swim test (FST)] were measured as a function of isolation. Isolation reduced sucrose intake and increased immobility in the FST; these behaviors also were prevented by oxytocin. Administration of oxytocin did not significantly alter cardiac, autonomic or behavioral responses of paired animals. These findings support the hypothesis that oxytocinergic mechanisms can protect against behavioral and cardiac dysfunction in response to chronic social stressors, and can provide insight into social influences on behavior and autonomic function in humans.

Introduction

The absence of positive social interactions and social support can contribute to alterations in behavior and physiology, including both negative mood states and cardiovascular dysfunction (Knox and Uvnäs-Moberg, 1998, Kiecolt-Glaser and Newton, 2001, Krantz and McCeney, 2002, Cacioppo et al., 2002). For instance, in humans perceived loneliness is associated with symptoms of depression and increased cardiovascular reactivity during exposure to a mental stressor (Steptoe et al., 2004). Maladaptive grief, affective disorders and autonomic dysfunction have been associated with the disruption of social bonds or perceived loneliness in humans (Prigerson et al., 1994, Cacioppo et al., 2002, Berkman et al., 2004). Social stressors also produce behavioral alterations and autonomic and cardiac dysfunction in non-human animals, using operational dependent measures that have been validated in rodents (Grippo et al., 2007b, Grippo et al., 2007d, Grippo et al., 2008). These data suggest that social stressors and the lack of positive social interactions significantly influence behavior and physiology in both humans and non-human animals. However, the mechanisms linking the absence of social interactions to mental and cardiovascular health remain to be described. Of particular interest in understanding the consequences of social stressors are neuroendocrine systems that regulate social bonding, mental health and autonomic function.

The mammalian neuropeptide, oxytocin, is highly sensitive to the social environment, and regulates behavior (including affective behaviors) and autonomic function (Uvnäs-Moberg, 1998, Carter, 2003, Michelini et al., 2003). However, the specific functions of oxytocin in the context of various social and environmental experiences are not well understood. Oxytocin has been shown to be released in specific central nervous system regions and in the circulation during positive social experiences, and has been suggested to facilitate positive social interactions including social memory, pair bonding, and parental behavior (Carter, 1998, Carter, 2003, Cho et al., 1999, Ferguson et al., 2000, Ferguson et al., 2001, Young and Wang, 2004). For instance, intracerebroventricular (ICV) administration of oxytocin (and also arginine vasopressin) led to increased positive social contact and an increased preference for a familiar social partner in both female and male prairie voles; these effects were blocked with pretreatment of either an oxytocin receptor antagonist or a vasopressin V1a receptor antagonist, suggesting that these related peptides may facilitate positive social behaviors if either the oxytocin or vasopressin receptor is available (Cho et al., 1999).

However, increased levels of oxytocin both in the central and peripheral nervous system also have been associated with stressful events in humans and rodents (Gibbs, 1984, Nishioka et al., 1998, Taylor et al., 2006, Grippo et al., 2007b). For example, higher plasma levels of oxytocin in women were correlated with “gaps in social relationships,” lower overall quality of social interactions, and absence of positive relations with partners (Taylor et al., 2006). Several animal studies have shown related increases in endogenous oxytocin in response to stressful events. For example, oxytocin (but not vasopressin) was shown to be released specifically in the hypothalamic paraventricular nucleus (shown via microdialysis) and in the plasma during an acute shaker stress paradigm (10 min) in male rats (Nishioka et al., 1998). Similarly, oxytocin levels were increased both in the hypothalamic paraventricular nucleus (shown via immunohistochemical staining) and in the plasma following prolonged (4 weeks) social isolation versus pairing with a sibling in female prairie voles (Grippo et al., 2007b). Also, in prairie voles intense acute stressors, including the resident–intruder paradigm (Grippo et al., 2007a, Grippo et al., 2007b) and restraint (Pournajafi and Carter, unpublished observations), were associated with increases in plasma oxytocin. Finally, mice that are genetically deficient for oxytocin or its receptor have been shown to be highly reactive to psychogenic stressors such as shaker stress or restraint, although they continue to show normal reactions to physical stressors such as insulin-induced hypoglycemia (Mantella et al., 2004, Takayanagi et al., 2005).

These and other studies suggest that oxytocin is a component of an endogenous system with the capacity to buffer against both physical and emotional stressors (Uvnäs-Moberg, 1998, Carter, 1998, Neumann et al., 2000, Heinrichs et al., 2003). This system, regulated in part by oxytocin, appears to coordinate adaptive endocrine and autonomic reactions to stressors, possibly by upregulating parasympathetic and/or reducing sympathoadrenal responses (see for instance Porges, 1998, Porges, 2001, Porges, 2007).

Studies that focus on the consequences of social stressors and the role of peptides using valid and relevant animal models will promote a greater understanding of the social factors that contribute to behavioral and autonomic dysregulation. The socially monogamous prairie vole is a rodent species that exhibits social behaviors that parallel those observed in humans, including an active engagement in and reliance on the social environment, living in pairs or family groups, and displaying bi-parental care of offspring (Carter et al., 1995, Getz and Carter, 1996, Carter and Keverne, 2002). The behavioral, autonomic, and cardiac consequences of negative social stressors in this species are only recently being investigated. Prairie voles are highly sensitive to social isolation from either a same-sex sibling or an opposite-sex partner; following short- or long-term isolation prairie voles show alterations in behaviors that may be relevant to depression, including immobility in a forced swim test (FST) and reduced responsiveness to a rewarding stimulus (Grippo et al., 2008, Bosch et al., 2008). Research from our laboratories also demonstrates that long-term social isolation in prairie voles (vs. pairing with a sibling of the same sex) produces several autonomic and cardiac disruptions indicative of potential cardiovascular pathophysiology, including increased resting heart rate (HR), reduced HR variability, increased cardiac responsiveness to acute stressors, disrupted sympathovagal balance, and increased heart weight (Grippo et al., 2007d).

Given the utility of the prairie vole model for experimental investigations of behavioral and physiological responses to social experiences, the present study was designed to investigate the effects of exogenously administered oxytocin in mediating behavioral, autonomic, and cardiac responses in female prairie voles exposed to long-term social isolation. The present study builds upon previous research showing that female prairie voles are especially sensitive to social isolation (Grippo et al., 2007b, Grippo et al., 2007d, Grippo et al., 2008), and that oxytocin may be of particular importance in regulating behavioral and physiological responses to stressors (Uvnäs-Moberg, 1998, Carter, 1998, Neumann et al., 2000, Heinrichs et al., 2003, Grippo et al., 2007b). We conducted two parallel experiments to investigate the hypothesis that negative autonomic (Experiment 1) and behavioral (Experiment 2) consequences, which typically follow 2–4 weeks of social isolation in adult, female prairie voles, would be prevented by long-term peripheral administration of exogenous oxytocin.

Section snippets

Animals

Female prairie voles (Microtus ochrogaster) – 60–90 days of age, 35–55 g in weight, descendants of a wild stock caught near Champaign, Illinois – were maintained on a 14/10 h light/dark cycle (lights on at 0630 h), with a temperature of 25 ± 1 °C and relative humidity of 21 ± 4 g/m3. Food (Purina rabbit chow) and water were available ad libitum unless otherwise specified. Offspring were removed from breeding pairs at 21 days of age and housed in same-sex sibling pairs; only one sibling from each pair

Resting cardiac parameters

The following group names are used herein: Paired + Vehicle (V), Paired + Oxytocin (OT), Isolated + V, and Isolated + OT. Isolation significantly increased resting HR and reduced HR variability (both SDNN index and RSA amplitude) relative to control conditions; these changes were prevented by oxytocin administration (Fig. 1).

The ANOVA for resting HR yielded a 3-way interaction among time × group × peptide [F(1,22) = 8.30, P < .05]; and main effects of group [F(1,22) = 8.72, P < .05] and peptide [F(1,22) = 9.90, P < 

Discussion

Previous research in humans and prairie voles suggests that long-term social stressors produce behavioral changes, some of which may be relevant to depression, as well as autonomic dysfunction indicative of potential cardiac pathophysiology (Kiecolt-Glaser and Newton, 2001, Krantz and McCeney, 2002, Cacioppo et al., 2002, Grippo et al., 2007d, Grippo et al., 2008). Further, the oxytocinergic system may be activated under certain stressful conditions (e.g., during long-term isolation), possibly

Role of the funding source

Funding for this research was provided by NIMH grants MH67446, MH72935, MH73233, and MH77581. The NIMH had no further role in the study design, data collection, analysis and interpretation of data, writing of the report, or decision to submit the paper for publication.

Conflict of interest

None declared.

Acknowledgements

This research was funded by National Institutes of Health grants MH67446 (SWP), MH72935 (CSC), MH73233 (AJG), and MH77581 (AJG). The investigators thank Iman Hassan, Damon Lamb, Gregory Lewis, Lisa Sanzenbacher, Eric Schmidt, Maulin Shah, and Patrin Suppatkul for valuable assistance.

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