Elsevier

Psychoneuroendocrinology

Volume 42, April 2014, Pages 225-236
Psychoneuroendocrinology

Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice

https://doi.org/10.1016/j.psyneuen.2014.01.021Get rights and content

Abstract

Chronic psychosocial stress is a recognized risk factor for various affective and somatic disorders. In an established murine model of chronic psychosocial stress, exposure to chronic subordinate colony housing (CSC) results in an alteration of physiological, behavioral, neuroendocrine and immunological parameters, including a long-lasting increase in anxiety, adrenal hypertrophy and thymus atrophy. Based on the stress-protective and anxiolytic properties of oxytocin (OXT) after acute administration in rodents and humans, the major aims of our study were to assess whether chronic administration of OXT dose-dependently affects the behavior and physiology of male mice, as for therapeutic use in humans, mostly chronic treatment approaches will be used. Further, we studied, whether chronic administration during CSC prevents stress-induced consequences. Our results indicate that chronic intracerebroventricular (ICV) infusion of OXT (15 days) at high (10 ng/h), but not at low (1 ng/h) dose, induces an anxiogenic phenotype with a concomitant reduction of OXT receptor (OXTR) binding within the septum, the basolateral and medial amygdala, as well as the median raphe nucleus. Further, we demonstrate that chronic ICV infusion of OXT (1 ng/h) during a 19-day CSC exposure prevents the hyper-anxiety, thymus atrophy, adrenal hypertrophy, and decreased in vitro adrenal ACTH sensitivity. Thus, given both negative, but also beneficial effects seen after chronic OXT treatment, which appear to be dose-dependent, a deeper understanding of long-lasting treatment effects is required before OXT can be considered for long-term therapeutic use for the treatment of psychopathologies such as autism, schizophrenia or anxiety-disorders.

Introduction

In modern societies, chronic psychosocial stress has repeatedly been related to the etiology of numerous somatic diseases, such as inflammatory bowel disease (Duffy et al., 1991, Levenstein et al., 2000) or cancer (Reiche et al., 2004), and depression- and anxiety-related (Shalev, 2009) disorders. In clinically relevant animal models a link between repeated or chronic psychosocial stress and emotional, physiological, and immunological adaptations has been demonstrated (Berton et al., 2006, Reber et al., 2007, Stefanski et al., 2001). Chronic subordinate colony housing (CSC) of male mice represents such a validated mouse model of chronic psychosocial stress. Exposure to CSC reliably affects stress-related parameters (Peters et al., 2012, Peters et al., 2013, Reber et al., 2011, Slattery et al., 2012), reflecting the situation in humans who experience chronic stressful life events (Levenstein et al., 2000, Reiche et al., 2004). Due to the omnipresence of psychosocial stress on the one hand and limited treatment options on the other, the development of new therapeutics for stress-related pathologies is highly needed. In this context, neuropeptides have emerged as such promising novel targets (Griebel and Holsboer, 2012, Macdonald and Feifel, 2012, Neumann and Landgraf, 2012, Slattery and Neumann, 2010b).

One such candidate is the nonapeptide oxytocin (OXT), which is synthesized in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. Following acute application, OXT has been shown to exert anxiolytic and stress-protective effects in rodents (Bale et al., 2001, Blume et al., 2008, Jurek et al., 2012, Viviani et al., 2011) and humans (Guastella et al., 2009, Heinrichs et al., 2001, Kirsch et al., 2005); Meyer-Lindenberg et al., 2011, Neumann and Landgraf, 2012). In this context, pharmaco-genetic manipulation of the brain OXT system in rats and mice revealed a direct inhibitory effect on the (re)activity of the hypothalamo–pituitary–adrenal (HPA) axis and on anxiety, and promotion of an active stress-coping style (Amico et al., 2004, Neumann and Landgraf, 2012, Neumann et al., 2000, Sala et al., 2011, Windle et al., 1997). The areas via which OXT exerts these effects could be localized within amygdala and septal regions, the raphe nucleus and the hypothalamic PVN (Guzman et al., 2013, Jurek et al., 2012, Knobloch et al., 2012, Neumann et al., 2000, Viviani et al., 2011, Yoshida et al., 2009). Moreover, OXT promotes social behaviors in rodents and humans including social bonding, social recognition and social preference (Donaldson and Young, 2008, Lukas and Neumann, 2013). The effects described above make OXT a promising candidate for preventing, or attenuating, the negative consequences of chronic psychosocial stress.

In humans, there is growing interest in the intranasal application of OXT due to a series of promising effects on emotionality, stress responsiveness and social behavior (Guastella et al., 2009, Heinrichs et al., 2003, Kirsch et al., 2005). Therefore, intranasal OXT has become an attractive treatment option for anxiety- and stress-related disorders, autism and schizophrenia, which are likely to require repeated or chronic treatment. However, in most studies to date, only acute application of OXT has been studied. Thus, it is essential to investigate the behavioral, physiological and molecular effects of long-term OXT administration, especially chronic OXT effects on the endogenous OXT system. The few rodent studies assessing such repeated or chronic administration have reported inconsistent results, with some reporting beneficial (Grippo et al., 2012, Slattery and Neumann, 2010a, Windle et al., 2004, Windle et al., 1997) and others more negative (Bales et al., 2012) effects. For example, intracerebroventricular (ICV) OXT infusion using osmotic minipumps (OMP) at either 1, 10 or 100 ng/h for 5 consecutive days dose-dependently reduced anxiety and HPA axis responsiveness to acute stress including hypothalamic CRF expression in female rats (Windle et al., 2004, Windle et al., 1997). In line, chronic ICV OXT (10 ng/h) infusion for six days was shown to reduce anxiety in female Wistar rats selectively bred for high anxiety-related behavior (HAB) (Slattery and Neumann, 2010a). In contrast to those beneficial effects of chronic or repeated central OXT infusion, Bales et al. (2012) report impaired partner preference formation in male prairie voles after a daily intranasal OXT application over 3 weeks. However, none of these studies have examined the impact of chronic up-regulation of central OXT availability on the endogenous neuropeptide system, which is of particular importance given the potential long-lasting or even chronic therapeutic use of OXT in various psychopathological disorders.

Thus, the major aims of the current study were to investigate, whether chronic ICV infusion of OXT using OMP dose-dependently affects physiological and behavioral parameters and the endogenous OXT system under basal conditions, and whether chronic OXT can reduce chronic stress-induced alterations in male mice.

Section snippets

Animals

Male C57BL/6 mice (Charles River, Sulzfeld, Germany) weighing 19–22 g (experimental mice) or 30–35 g (dominant mice) were individually housed in standard polycarbonate mouse cages (16 × 22 × 14 cm) for one week before the start of CSC exposure. All mice were kept under standard laboratory conditions (12 h light/dark cycle, lights on at 0600 h, 22 °C, 60% humidity) with free access to tap water and standard mouse diet. All experimental protocols were approved by the Committee on Animal Health and Care of

Experiment 1: Effects of OMP surgery on CSC-induced anxiety and physiological parameters

There was a main effect of CSC on EPM anxiety (F1,26 = 21.8; p < 0.001), body weight gain (F1,26 = 15.8; p < 0.001), relative adrenal (F1,26 = 19.8; p < 0.001) and thymus (F1,26 = 20.1; p < 0.001) weight, and histological damage score of the colon (F1,26 = 7.85; p < 0.01).

Post-hoc Bonferroni pairwise comparisons revealed an increased anxiety-related behavior in CSC compared with SHC mice independent of prior OMP surgery. In detail, both CSC-NS and CSC-OMP mice spent less time on the open arms of the EPM compared

Discussion

In the present study, we demonstrate that chronic ICV infusion of OXT in mice (i) increases anxiety and reduces OXTR binding in several stress-and anxiety-related brain regions at high dose, but (ii) can also be beneficial and protect against chronic stress-induced behavioral and physiological alterations at a low dose. In more detail, continuous central infusion of a high (10 ng/h), but not low (1 ng/h), dose of OXT via OMP over 15 days increased anxiety-related behavior on the EPM and in the

Role of funding source

This work was supported by research grants from the Deutsche Forschungsgemeinschaft to IDN, SOR and DAS, and by the Elitenetwork of Bavaria.

Conflict of interest

The authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

Acknowledgments

The authors are grateful to G. Schindler, M. Fuchs, N. Grunwald, R. Kokel and D. Fiedler for technical and practical help. Supported by research grants from the Deutsche Forschungsgemeinschaft (IDN, SOR), and by the Elitenetwork of Bavaria.

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  • Cited by (0)

    1

    Current address: Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, 89081 Ulm, Germany.

    2

    These authors contributed equally.

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