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

Peters, Sebastian; Slattery, David A.; Uschold-Schmidt, Nicole; Reber, Stefan O.; Neumann, Inga D.

doi:10.1016/j.psyneuen.2014.01.021

Cited by 152 publications

(131 citation statements)

References 63 publications

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“…While our data implicate OXT as a treatment option for disorders associated with social fear, such as SAD, more detailed studies regarding acute and long-term treatment effects on molecular, neuronal, and behavioral levels are required. This is more evident as chronic central as well as peripheral OXT treatment in mice affected brain OXTR binding (Huang et al, 2013;Peters et al, 2014).…”

Section: Discussionmentioning

confidence: 97%

Brain Oxytocin in Social Fear Conditioning and Its Extinction: Involvement of the Lateral Septum

Zoicas

Slattery

Neumann

2014

Neuropsychopharmacol

154

160

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Central oxytocin (OXT) has anxiolytic and pro-social properties both in humans and rodents, and has been proposed as a therapeutic option for anxiety and social dysfunctions. Here, we utilized a mouse model of social fear conditioning (SFC) to study the effects of OXT on social fear, and to determine whether SFC causes alterations in central OXT receptor (OXTR) binding and local OXT release. Central infusion of OXT, but not arginine vasopressin, prior to social fear extinction training completely abolished social fear expression in an OXTR-mediated fashion without affecting general anxiety or locomotion. SFC caused increased OXTR binding in the dorso-lateral septum (DLS), central amygdala, dentate gyrus, and cornu ammunis 1, which normalized after social fear extinction, suggesting that these areas form part of a brain network involved in the development and neural support of social fear. Microdialysis revealed that the increase in OXT release observed in unconditioned mice within the DLS during social fear extinction training was attenuated in conditioned mice. Consequently, increasing the availability of local OXT by infusion of OXT into the DLS reversed social fear. Thus, alterations in the brain OXT system, including altered OXTR binding and OXT release within the DLS, play an important role in SFC and social fear extinction. Thus, we suggest that the OXT system is adversely affected in disorders associated with social fear, such as social anxiety disorder and reinstalling an appropriate balance of the OXT system may alleviate some of the symptoms.

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Section: Discussionmentioning

confidence: 97%

Brain Oxytocin in Social Fear Conditioning and Its Extinction: Involvement of the Lateral Septum

Zoicas

Slattery

Neumann

2014

Neuropsychopharmacol

154

160

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“…Chronic i.c.v. injection of high OT doses in mice produced higher anxiety-like behavior in a social stress paradigm, which was paralleled by reductions in OTR binding in various brain areas (e.g., amygdala, septum) relevant for stress-regulation (Peters et al, 2014). Similarly, chronic intranasal OT treatment resulted in a reduction of social behaviors and concurrent reductions of OTR binding in the nAcc, amygdala, and anterior olfactory nucleus amongst other brain regions (Huang et al, 2014).…”

Section: Methodological Challenges Future Directions and Translatmentioning

confidence: 99%

Oxytocin pathways in the intergenerational transmission of maternal early life stress

Toepfer

Heim

Entringer

et al. 2017

Neuroscience & Biobehavioral Reviews

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Severe stress in early life, such as childhood abuse and neglect, constitutes a major risk factor in the etiology of psychiatric disorders and somatic diseases. Importantly, these long-term effects may impact the next generation. The intergenerational transmission of maternal early life stress (ELS) may occur via pre-and postnatal pathways, such as alterations in maternal-fetal-placental stress physiology, maternal depression during pregnancy and postpartum, as well as impaired mother-offspring interactions. The neuropeptide oxytocin (OT) has gained considerable attention for its role in modulating all of these assumed transmission pathways. Moreover, central and peripheral OT signaling pathways are highly sensitive to environmental exposures and may be compromised by ELS with implications for these putative transmission mechanisms. Together, these data suggest that OT pathways play an important role in the intergenerational transmission of maternal ELS in humans. By integrating recent studies on gene-environment interactions and epigenetic modifications in OT pathway genes, the present review aims to develop a conceptual framework of intergenerational transmission of maternal ELS that emphasizes the role of OT.

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“…However, relevant basic studies are rare, and those performed reveal that chronic OXT effects strongly depend on the dose and duration of application, are likely to vary between male and female subjects (65)(66)(67)(68)(69)(70)(71)(72), and are dependent upon the innate level of anxiety (65). For example, in male mice, chronic icv infusion of OXT (10 ng/hour) over 2 weeks induced a robust increase in anxiety-related behavior in two independent behavioral tests, whereas a tenfold lower dose did not alter anxiety (67). In contrast, in ovariectomized, steroid-treated female rats, 5 days of icv OXT (10 ng/hour) reduced anxiety levels and stress-induced c-Fos activation in relevant brain regions (66,72).…”

Section: Chronic Effects Of Synthetic Oxt On Anxietymentioning

confidence: 99%

“…Importantly, chronic icv infusion as well as repeated (twice daily) nasal application of synthetic OXT were found to affect the endogenous OXT system by reducing OXT-R binding in several brain regions relevant for anxiety regulation (septum, amygdala, median raphe nucleus, nucleus accumbens, hippocampus) (67,68). These findings follow a general principle in neuropharmacology in that persistent agonist stimulation by chronic exposure to the receptor ligand, OXT in this case, results in downregulation and desensitization of receptors (74).…”

Section: Chronic Effects Of Synthetic Oxt On Anxietymentioning

confidence: 99%

Oxytocin in General Anxiety and Social Fear: A Translational Approach

Neumann

Slattery

2016

Biological Psychiatry

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366

276

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The neuropeptide oxytocin (OXT) has been revealed as a profound anxiolytic and antistress factor of the brain, besides its many prosocial and reproductive effects. Therefore, there is substantial scientific and medical interest in its potential therapeutic use for the treatment of psychopathologies associated with anxiety, fear, and social dysfunctions, such as generalized anxiety disorder, posttraumatic stress disorder, and social anxiety disorder, as well as autism and schizophrenia, among others. Focusing on preclinical studies, we review the existing evidence for the regulatory capacity of OXT to fine-tune general and social anxiety-related behaviors, as well as cued and social fear conditioning from a translational perspective. The available evidence from animal and human studies substantiates the hypothesis of an imbalance of the endogenous brain OXT system in the etiology of anxiety disorders, particularly those with a social component such as social anxiety disorder. In addition, such an imbalance of the OXT system is also likely to be the consequence of chronic OXT treatment resulting in a dose-dependent reduction in OXT receptor availability and increased anxiety.

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

Cited by 152 publications

References 63 publications

Brain Oxytocin in Social Fear Conditioning and Its Extinction: Involvement of the Lateral Septum

Brain Oxytocin in Social Fear Conditioning and Its Extinction: Involvement of the Lateral Septum

Oxytocin pathways in the intergenerational transmission of maternal early life stress

Oxytocin in General Anxiety and Social Fear: A Translational Approach

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