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Oxytocin in General Anxiety and Social Fear: A Translational Approach

  • Inga D. Neumann
    Correspondence
    Address correspondence to Inga D. Neumann, University of Regensburg, Department of Behavioral and Molecular Neurobiology, Universitaetsstr. 31, Regensburg, 93040, Germany
    Affiliations
    Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany
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  • David A. Slattery
    Affiliations
    Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany
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Open AccessPublished:June 10, 2015DOI:https://doi.org/10.1016/j.biopsych.2015.06.004

      Abstract

      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.

      Keywords

      Anxiety disorders, such as generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and social anxiety disorder (SAD), are among the most common psychiatric illnesses with a lifetime prevalence of approximately 30% (
      • Kessler R.C.
      • Wang P.S.
      The descriptive epidemiology of commonly occurring mental disorders in the United States.
      ). GAD is defined as a persistent and unnecessary anxiety of everyday life and/or events for a period of at least 6 months. The main treatment options for GAD are benzodiazepines and beta blockers or drugs originally used for major depressive disorder. SAD and PTSD, the second and third most prevalent anxiety disorders, respectively, are largely characterized by fear of a previously encountered situation (
      • Alonso J.
      • Petukhova M.
      • Vilagut G.
      • Chatterji S.
      • Heeringa S.
      • Ustun T.B.
      • et al.
      Days out of role due to common physical and mental conditions: Results from the WHO World Mental Health surveys.
      ,
      • Kessler R.C.
      • Petukhova M.
      • Sampson N.A.
      • Zaslavsky A.M.
      • Wittchen H.U.
      Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States.
      ). PTSD occurs in a subset of people who have witnessed, or experienced, a traumatic event, such as war or personal assault, and is manifest as flashbacks of the event or, in more serious cases, generalization of the event to similar contexts. In contrast, SAD, also often referred to as social phobia, is characterized by the persistent fear and avoidance of social situations (
      • Toth I.
      • Neumann I.D.
      Animal models of social avoidance and social fear.
      ). There are two main forms of SAD: specific SAD, which is described as fear and avoidance of particular social situations and interactions (e.g., fear of public speaking) (
      • Bogels S.M.
      • Alden L.
      • Beidel D.C.
      • Clark L.A.
      • Pine D.S.
      • Stein M.B.
      • Voncken M.
      Social anxiety disorder: Questions and answers for the DSM-V.
      ), and generalized SAD, characterized by the avoidance of all social situations (
      • den Boer J.A.
      Social phobia: Epidemiology, recognition, and treatment.
      ,
      • Kessler R.C.
      • Stein M.B.
      • Berglund P.
      Social phobia subtypes in the National Comorbidity Survey.
      ,
      • Ruipérez M.A.
      • Garcia-Palacios A.
      • Botella C.
      Clinical features and treatment response in social phobia: Axis II comorbidity and social phobia subtypes.
      ). Treatment for PTSD and SAD is rather unspecific and involves cognitive psychotherapy in combination with pharmacotherapies originally designed for depression or GAD.
      These anxiety disorders are highly comorbid with other affective disorders, including major depressive disorder, autism, or Prader-Willi-syndrome (
      • Chartier M.J.
      • Walker J.R.
      • Stein M.B.
      Considering comorbidity in social phobia.
      ,
      • Schneier F.R.
      • Foose T.E.
      • Hasin D.S.
      • Heimberg R.G.
      • Liu S.M.
      • Grant B.F.
      • Blanco C.
      Social anxiety disorder and alcohol use disorder co-morbidity in the National Epidemiologic Survey on Alcohol and Related Conditions.
      ). Interestingly, symptoms of SAD often emerge first, indicating that SAD may be a major risk factor for other psychiatric disorders. Therefore, early specific intervention of social fear might reduce the risk of comorbidities. However, treatment of anxiety disorders generally achieves only partial remission of symptoms or shows a high rate of relapse (
      • Blanco C.
      • Bragdon L.B.
      • Schneier F.R.
      • Liebowitz M.R.
      The evidence-based pharmacotherapy of social anxiety disorder.
      ), highlighting the necessity for more specific treatment options. Recently, neuropeptides have emerged as viable candidates, such as oxytocin (OXT), arginine vasopressin (AVP) (
      • Landgraf R.
      • Gerstberger R.
      • Montkowski A.
      • Probst J.C.
      • Wotjak C.T.
      • Holsboer F.
      • Engelmann M.
      V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats.
      ) [for reviews, see (
      • Frank E.
      • Landgraf R.
      The vasopressin system--from antidiuresis to psychopathology.
      ,
      • Landgraf R.
      • Neumann I.D.
      Vasopressin and oxytocin release within the brain: A dynamic concept of multiple and variable modes of neuropeptide communication.
      )], neuropeptide Y (
      • Wu G.
      • Feder A.
      • Wegener G.
      • Bailey C.
      • Saxena S.
      • Charney D.
      • Mathé A.A.
      Central functions of neuropeptide Y in mood and anxiety disorders.
      ), and neuropeptide S (
      • Slattery D.A.
      • Naik R.R.
      • Grund T.
      • Yen Y.-C.
      • Sartori S.B.
      • Füchsl A.
      • et al.
      Selective breeding for high anxiety introduces a synonymous SNP that increases neuropeptide S receptor activity.
      ,
      • Meis S.
      • Bergado-Acosta J.R.
      • Yanagawa Y.
      • Obata K.
      • Stork O.
      • Munsch T.
      Identification of a neuropeptide S responsive circuitry shaping amygdala activity via the endopiriform nucleus.
      ,
      • Lukas M.
      • Neumann I.D.
      Nasal application of neuropeptide S reduces anxiety and prolongs memory in rats: Social versus non-social effects.
      ).

      Brief Overview of The Brain Oxt System As A Potential Therapeutic Target

      The first reported behavioral effects of the two closely related neurohypophysial nonapeptides OXT and AVP date back to the 1960s and 1970s, when effects on maternal behavior (
      • Pedersen C.A.
      • Prange Jr, A.J.
      Induction of maternal behavior in virgin rats after intracerebroventricular administration of oxytocin.
      ) and on memory functions (
      • De Wied D.
      The influence of the posterior and intermediate lobe of the pituitary and pituitary peptides on the maintenance of a conditioned avoidance response in rats.
      ), respectively, were described. From a translational view, AVP first predominated scientific interest due to its anxiogenic and depressive-like effects [for review, see (
      • Frank E.
      • Landgraf R.
      The vasopressin system--from antidiuresis to psychopathology.
      ,
      • Neumann I.D.
      • Landgraf R.
      Balance of brain oxytocin and vasopressin: Implications for anxiety, depression, and social behaviors.
      )]. However, despite the development of various nonpeptidergic AVP receptor antagonists, research in this direction has almost halted due to a lack of clinical efficacy. In contrast, the discovery of anxiolytic, antistress, and prosocial effects of OXT in rodents in the 1990s has promoted a switch to this nonapeptide. This has further been facilitated by the discovery of a plethora of OXT effects after intranasal application in humans [see below and (
      • MacDonald K.
      • Feifel D.
      Oxytocin’s role in anxiety: A critical appraisal.
      ,
      • Meyer-Lindenberg A.
      • Domes G.
      • Kirsch P.
      • Heinrichs M.
      Oxytocin and vasopressin in the human brain: Social neuropeptides for translational medicine.
      )].
      The physiology of the hypothalamic-neurohypophysial system and its main neuropeptides OXT and AVP has become a textbook example. Briefly, the synthesis of OXT and AVP in magnocellular neurons located within the supraoptic (SON), paraventricular (PVN), and accessory nuclei of the hypothalamus (
      • Rhodes C.H.
      • Morrell J.I.
      • Pfaff D.W.
      Immunohistochemical analysis of magnocellular elements in rat hypothalamus: Distribution and numbers of cells containing neurophysin, oxytocin, and vasopressin.
      ); the electrophysiological properties of such neurons; stimuli triggering their peripheral secretion into blood; and subsequent physiological functions are well defined. Moreover, although our knowledge regarding other sites of neuronal synthesis, neuropeptidergic circuitries (
      • De Vries G.J.
      • Buijs R.M.
      The origin of the vasopressinergic and oxytocinergic innervation of the rat brain with special reference to the lateral septum.
      ,
      • Knobloch H.S.
      • Grinevich V.
      Evolution of oxytocin pathways in the brain of vertebrates.
      ) and region- and stimulus-dependent central release patterns (
      • Landgraf R.
      • Neumann I.D.
      Vasopressin and oxytocin release within the brain: A dynamic concept of multiple and variable modes of neuropeptide communication.
      ,
      • Knobloch H.S.
      • Grinevich V.
      Evolution of oxytocin pathways in the brain of vertebrates.
      ,
      • Neumann I.D.
      Stimuli and consequences of dendritic release of oxytocin within the brain.
      ) is continuously rising, many aspects are still a matter of intense research interest. For example, the subcellular location of OXT receptors (OXT-R) at either axosynaptic, dendritic or somatic fractions; the dynamics of local receptor expression and binding; and associated intracellular signaling cascades that determine—possibly sex-dependent—OXT actions are largely unknown (
      • Gimpl G.
      • Fahrenholz F.
      The oxytocin receptor system: Structure, function, and regulation.
      ,
      • van den Burg E.H.
      • Neumann I.D.
      Bridging the gap between GPCR activation and behaviour: Oxytocin and prolactin signalling in the hypothalamus.
      ). Such details are essentially needed before OXT can be considered a routine treatment option for anxiety-related diseases or social dysfunctions.

      Oxt Involvement In Anxiety-Related Behavior

      Responsiveness of the OXT System to Anxiety and Stress

      Anxiogenic and stressful stimuli significantly activate the body’s OXT system, as reflected by increased electrophysiological activity of OXT neurons, increased OXT gene expression within the SON and PVN, and stimulated peripheral and intracerebral OXT release (
      • Gibbs D.M.
      Dissociation of oxytocin, vasopressin and corticotropin secretion during different types of stress.
      ,
      • Williams T.D.
      • Carter D.A.
      • Lightman S.L.
      Sexual dimorphism in the posterior pituitary response to stress in the rat.
      ,
      • Lang R.E.
      • Heil J.W.
      • Ganten D.
      • Hermann K.
      • Unger T.
      • Rascher W.
      Oxytocin unlike vasopressin is a stress hormone in the rat.
      ,
      • Onaka T.
      • Yagi K.
      Effects of novelty stress on vasopressin and oxytocin secretion by the pituitary in the rat.
      ,
      • Jezova D.
      • Skultetyova I.
      • Tokarev D.I.
      • Bakos P.
      • Vigas M.
      Vasopressin and oxytocin in stress.
      ,
      • Wotjak C.T.
      • Ganster J.
      • Kohl G.
      • Holsboer F.
      • Landgraf R.
      • Engelmann M.
      Dissociated central and peripheral release of vasopressin, but not oxytocin, in response to repeated swim stress: New insights into the secretory capacities of peptidergic neurons.
      ) [for review, see (
      • Landgraf R.
      • Neumann I.D.
      Vasopressin and oxytocin release within the brain: A dynamic concept of multiple and variable modes of neuropeptide communication.
      ,
      • Neumann I.D.
      Stimuli and consequences of dendritic release of oxytocin within the brain.
      ,
      • Engelmann M.
      • Landgraf R.
      • Wotjak C.T.
      The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: An old concept revisited.
      )]. For example, exposure of male rats to novelty, forced swimming, or social defeat rapidly increases OXT release into blood but also within the PVN and/or SON and in other limbic brain regions, such as the central amygdala or septum (
      • Neumann I.D.
      Stimuli and consequences of dendritic release of oxytocin within the brain.
      ,
      • Engelmann M.
      • Landgraf R.
      • Wotjak C.T.
      The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: An old concept revisited.
      ). Similarly, increased OXT release into blood (
      • Neumann I.D.
      • Toschi N.
      • Ohl F.
      • Torner L.
      • Kromer S.A.
      Maternal defence as an emotional stressor in female rats: Correlation of neuroendocrine and behavioural parameters and involvement of brain oxytocin.
      ) and within the PVN and central amygdala (
      • Bosch O.J.
      • Kromer S.A.
      • Brunton P.J.
      • Neumann I.D.
      Release of oxytocin in the hypothalamic paraventricular nucleus, but not central amygdala or lateral septum in lactating residents and virgin intruders during maternal defence.
      ) has also been found in female rats exposed to psychosocial stress (maternal defeat by an aggressive lactating resident dam). Magnocellular OXT neurons within the PVN (or SON) themselves may provide the neuroanatomical basis for these observations: in addition to their projections to the neurohypophysis, they can also release OXT locally within the PVN (or SON) from dendrites and perikarya, as well as from axon collaterals that project to distinct brain regions, for example, the central amygdala (
      • Knobloch H.S.
      • Charlet A.
      • Hoffmann L.C.
      • Eliava M.
      • Khrulev S.
      • Cetin A.H.
      • et al.
      Evoked axonal oxytocin release in the central amygdala attenuates fear response.
      ,
      • Ludwig M.
      • Leng G.
      Dendritic peptide release and peptide-dependent behaviours.
      ). Thus, it is tempting to conclude that fearful and stressful events activate the OXT system and, consequently, both peripheral and central OXT release (
      • Neumann I.D.
      Stimuli and consequences of dendritic release of oxytocin within the brain.
      ,
      • Engelmann M.
      • Landgraf R.
      • Wotjak C.T.
      The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: An old concept revisited.
      ) [but see (
      • Engelmann M.
      • Ebner K.
      • Landgraf R.
      • Holsboer F.
      • Wotjak C.T.
      Emotional stress triggers intrahypothalamic but not peripheral release of oxytocin in male rats.
      )]. This is an important observation with implications for human studies, as it speaks in favor of peripheral OXT measures being a global biomarker for the general activity of the endogenous OXT system also, at least partly, reflecting the central (re)activity of an individual’s OXT system to stress. However, we have to be aware of the fact that plasma OXT may, at best, only roughly reflect the temporal dynamics of central release patterns, which was shown to substantially differ from peripheral release patterns of OXT (
      • Landgraf R.
      • Neumann I.D.
      Vasopressin and oxytocin release within the brain: A dynamic concept of multiple and variable modes of neuropeptide communication.
      ,
      • Neumann I.D.
      Stimuli and consequences of dendritic release of oxytocin within the brain.
      ,
      • Engelmann M.
      • Ebner K.
      • Landgraf R.
      • Holsboer F.
      • Wotjak C.T.
      Emotional stress triggers intrahypothalamic but not peripheral release of oxytocin in male rats.
      ,
      • Ludwig M.
      • Callahan M.F.
      • Neumann I.
      • Landgraf R.
      • Morris M.
      Systemic osmotic stimulation increases vasopressin and oxytocin release within the supraoptic nucleus.
      ,
      • Neumann I.
      • Landgraf R.
      • Bauce L.
      • Pittman Q.J.
      Osmotic responsiveness and cross talk involving oxytocin, but not vasopressin or amino acids, between the supraoptic nuclei in virgin and lactating rats.
      ). Further, plasma OXT necessarily ignores brain region-dependent events, which play an important role in the behavioral effects of OXT (see below).
      Whereas these OXT-related events are well-characterized in rodents, there are only a few human reports of stress- or anxiety-induced changes in plasma OXT, such as in response to physical exercise (running), psychosocial stress (e.g., separation), or fear (
      • Landgraf R.
      • Hacker R.
      • Buhl H.
      Plasma vasopressin and oxytocin in response to exercise and during a day-night cycle in man.
      ,
      • Pierrehumbert B.
      • Torrisi R.
      • Ansermet F.
      • Borghini A.
      • Halfon O.
      Adult attachment representations predict cortisol and oxytocin responses to stress.
      ,
      • Carson D.S.
      • Berquist S.W.
      • Trujillo T.H.
      • Garner J.P.
      • Hannah S.L.
      • Hyde S.A.
      • et al.
      Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children.
      ,
      • Holt-Lunstad J.
      • Birmingham W.
      • Light K.C.
      The influence of depressive symptomatology and perceived stress on plasma and salivary oxytocin before, during and after a support enhancement intervention.
      ). This is surprising given that plasma (or saliva) OXT is the only easily accessible biomarker of the human OXT system. However, reliable assays are an important prerequisite [for details, see (
      • Suraev A.S.
      • Bowen M.T.
      • Ali S.O.
      • Hicks C.
      • Ramos L.
      • McGregor I.S.
      Adolescent exposure to oxytocin, but not the selective oxytocin receptor agonist TGOT, increases social behavior and plasma oxytocin in adulthood.
      ,
      • Robinson K.J.
      • Hazon N.
      • Lonergan M.
      • Pomeroy P.P.
      Validation of an enzyme-linked immunoassay (ELISA) for plasma oxytocin in a novel mammal species reveals potential errors induced by sampling procedure.
      ) and Leng and Ludwig (
      • Leng G.
      • Ludwig M.
      Intranasal oxytocin: Myths and delusions.
      ), this issue]. In several published studies, the validity of OXT data obtained with enzyme-linked immunosorbent assay from plasma samples without prior extraction procedure is questionable; corresponding studies are, therefore, not listed here.

      Acute Anxiolytic Effects of OXT

      Once released within the brain, OXT acts as a key modulator of anxiety-related behaviors and hypothalamic-pituitary-adrenal axis activity (
      • Neumann I.D.
      • Torner L.
      • Wigger A.
      Brain oxytocin: Differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats.
      ,
      • Neumann I.D.
      • Wigger A.
      • Torner L.
      • Holsboer F.
      • Landgraf R.
      Brain oxytocin inhibits basal and stress-induced activity of the hypothalamo-pituitary-adrenal axis in male and female rats: Partial action within the paraventricular nucleus.
      ). Relatively simple pharmacologic approaches using intracerebroventricular (icv) or local (PVN, central amygdala, prefrontal cortex) administration of an OXT-R agonist or antagonist have consistently shown an anxiolytic effect of synthetic or endogenous OXT in male and female rodents (
      • Bale T.L.
      • Davis A.M.
      • Auger A.P.
      • Dorsa D.M.
      • McCarthy M.M.
      CNS region-specific oxytocin receptor expression: Importance in regulation of anxiety and sex behavior.
      ,
      • Blume A.
      • Bosch O.J.
      • Miklos S.
      • Torner L.
      • Wales L.
      • Waldherr M.
      • Neumann I.D.
      Oxytocin reduces anxiety via ERK1/2 activation: Local effect within the rat hypothalamic paraventricular nucleus.
      ,
      • Ring R.H.
      • Malberg J.E.
      • Potestio L.
      • Ping J.
      • Boikess S.
      • Luo B.
      • et al.
      Anxiolytic-like activity of oxytocin in male mice: Behavioral and autonomic evidence, therapeutic implications.
      ,
      • Mak P.
      • Broussard C.
      • Vacy K.
      • Broadbear J.H.
      Modulation of anxiety behavior in the elevated plus maze using peptidic oxytocin and vasopressin receptor ligands in the rat.
      ,
      • Jurek B.
      • Slattery D.A.
      • Maloumby R.
      • Hillerer K.
      • Koszinowski S.
      • Neumann I.D.
      • van den Burg E.H.
      Differential contribution of hypothalamic MAPK activity to anxiety-like behaviour in virgin and lactating rats.
      ,
      • Sabihi S.
      • Durosko N.E.
      • Dong S.M.
      • Leuner B.
      Oxytocin in the prelimbic medial prefrontal cortex reduces anxiety-like behavior in female and male rats.
      ). Particularly intriguing is the anxiolytic effect of endogenous brain OXT during periods of robust activation and increased central release, including lactation (
      • Neumann I.D.
      • Torner L.
      • Wigger A.
      Brain oxytocin: Differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats.
      ,
      • Jurek B.
      • Slattery D.A.
      • Maloumby R.
      • Hillerer K.
      • Koszinowski S.
      • Neumann I.D.
      • van den Burg E.H.
      Differential contribution of hypothalamic MAPK activity to anxiety-like behaviour in virgin and lactating rats.
      ,
      • Neumann I.
      • Russell J.A.
      • Landgraf R.
      Oxytocin and vasopressin release within the supraoptic and paraventricular nuclei of pregnant, parturient and lactating rats: A microdialysis study.
      ) and sexual activity in both male and female rodents (
      • Waldherr M.
      • Neumann I.D.
      Centrally released oxytocin mediates mating-induced anxiolysis in male rats.
      ,
      • Waldherr M.
      • Nyuyki K.
      • Maloumby R.
      • Bosch O.J.
      • Neumann I.D.
      Attenuation of the neuronal stress responsiveness and corticotrophin releasing hormone synthesis after sexual activity in male rats.
      ,
      • Nyuyki K.D.
      • Waldherr M.
      • Baeuml S.
      • Neumann I.D.
      Yes, I am ready now: Differential effects of paced versus unpaced mating on anxiety and central oxytocin release in female rats.
      ). In contrast, under nonreproductive and stress-free conditions (and thus low OXT system activity), we have never been able to reveal an anxiolytic effect of brain OXT using an OXT-R antagonist. Thus, endogenous OXT does not seem to play a major role in the maintenance of a basal level of anxiety, but rather comes into play during psychosocial or physiological activation of the system. Behavioral data from transgenic mice lacking OXT provide further support for the anxiolytic importance of brain OXT in anxiety regulation, as female knockout mice show greater anxiety-related behavior than their wild-type counterparts on the elevated plus maze (
      • Amico J.A.
      • Mantella R.C.
      • Vollmer R.R.
      • Li X.
      Anxiety and stress responses in female oxytocin deficient mice.
      ) (for a summary of these findings including doses and tests employed, please see Table 1).
      Table 1Summary of Rodent Studies Assessing the Effect of Acute, Repeated, or Chronic Application of Synthetic OXT on Anxiety-Related Behavior Including General Anxiety and Conditioned Fear Cited in Text
      Sex and SpeciesFindingReference
      Acute Studies
       General anxiety-related behavior
      OXT 1 μg; central amygdalaFemale Sprague Dawley ratsAnxiolytic; OF (trend on EPM)(
      • Bale T.L.
      • Davis A.M.
      • Auger A.P.
      • Dorsa D.M.
      • McCarthy M.M.
      CNS region-specific oxytocin receptor expression: Importance in regulation of anxiety and sex behavior.
      )
      OXT 1 μg; icvMale and female HAB ratsNo effect on LDB(
      • Slattery D.A.
      • Neumann I.D.
      Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats.
      )
      OXT 1 μg; icvFemale Wistar ratsNo effect on EPM(
      • Slattery D.A.
      • Neumann I.D.
      Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats.
      )
      OXT .1–.5 μg; icvMale CD1 miceNo effect on EPM(
      • Zoicas I.
      • Slattery D.A.
      • Neumann I.D.
      Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum.
      )
      OXT .1–10 μg; icvMale Swiss-Webster and BABL/c miceAnxiolytic (3 and 10 ug, FPT; 1 ug, EZM)(
      • Ring R.H.
      • Malberg J.E.
      • Potestio L.
      • Ping J.
      • Boikess S.
      • Luo B.
      • et al.
      Anxiolytic-like activity of oxytocin in male mice: Behavioral and autonomic evidence, therapeutic implications.
      )
      Carbetocin 10–100 μg; icvMale Sprague Dawley ratsAnxiolytic (32 and 100 μg; EPM)(
      • Mak P.
      • Broussard C.
      • Vacy K.
      • Broadbear J.H.
      Modulation of anxiety behavior in the elevated plus maze using peptidic oxytocin and vasopressin receptor ligands in the rat.
      )
      Atosiban 1 mg/kg; ivMale Sprague Dawley ratsAnxiolytic; EPM(
      • Mak P.
      • Broussard C.
      • Vacy K.
      • Broadbear J.H.
      Modulation of anxiety behavior in the elevated plus maze using peptidic oxytocin and vasopressin receptor ligands in the rat.
      )
      Carbetocin 2.5–5 mg/kg; ivMale Sprague Dawley ratsNo effect on the EPM(
      • Mak P.
      • Broussard C.
      • Vacy K.
      • Broadbear J.H.
      Modulation of anxiety behavior in the elevated plus maze using peptidic oxytocin and vasopressin receptor ligands in the rat.
      )
      OXT 1–30 mg/kg; ipMale C57BL/6N and Swiss-Webster miceAnxiolytic (1–10 mg/kg; SIH [C57BL/6N]; 10 mg/kg; FPT [Swiss])(
      • Ring R.H.
      • Malberg J.E.
      • Potestio L.
      • Ping J.
      • Boikess S.
      • Luo B.
      • et al.
      Anxiolytic-like activity of oxytocin in male mice: Behavioral and autonomic evidence, therapeutic implications.
      )
      OXT .01 nmol; PVNMale and female Wistar ratsAnxiolytic; EPM (male) and LDB (male and female)(
      • Blume A.
      • Bosch O.J.
      • Miklos S.
      • Torner L.
      • Wales L.
      • Waldherr M.
      • Neumann I.D.
      Oxytocin reduces anxiety via ERK1/2 activation: Local effect within the rat hypothalamic paraventricular nucleus.
      ,
      • Jurek B.
      • Slattery D.A.
      • Maloumby R.
      • Hillerer K.
      • Koszinowski S.
      • Neumann I.D.
      • van den Burg E.H.
      Differential contribution of hypothalamic MAPK activity to anxiety-like behaviour in virgin and lactating rats.
      )
      OXT 5 ng; dorsolateral septumMale CD1 miceNo effect on EPM(
      • Zoicas I.
      • Slattery D.A.
      • Neumann I.D.
      Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum.
      )
      OXT .1–1 μg; prelimbic cortexMale and female Sprague Dawley ratsAnxiolytic (1 ug, EPM)(
      • Sabihi S.
      • Durosko N.E.
      • Dong S.M.
      • Leuner B.
      Oxytocin in the prelimbic medial prefrontal cortex reduces anxiety-like behavior in female and male rats.
      )
      OXT-R antagonist .75 μg; icvVirgin, pregnant, and lactating Wistar ratsAnxiogenic; EPM ( pregnant and lactating rats)(
      • Neumann I.D.
      • Torner L.
      • Wigger A.
      Brain oxytocin: Differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats.
      )
      OXT-R antagonist .75 μg; icvMale Wistar ratsNo effect on LDB(
      • Lukas M.
      • Toth I.
      • Reber S.O.
      • Slattery D.A.
      • Veenema A.H.
      • Neumann I.D.
      The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice.
      )
      OXT-R antagonist .75 μg; icvMale and female LAB ratsNo effect on EPM or LDB(
      • Slattery D.A.
      • Neumann I.D.
      Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats.
      )
      OXT-R antagonist .75 μg; icvMale CD1 miceNo effect on EPM(
      • Lukas M.
      • Toth I.
      • Reber S.O.
      • Slattery D.A.
      • Veenema A.H.
      • Neumann I.D.
      The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice.
      )
      OXT-R antagonist .75 μg; icvMale and Female Wistar ratsAttenuation of mating-induced anxiolysis(
      • Waldherr M.
      • Neumann I.D.
      Centrally released oxytocin mediates mating-induced anxiolysis in male rats.
      ,
      • Nyuyki K.D.
      • Waldherr M.
      • Baeuml S.
      • Neumann I.D.
      Yes, I am ready now: Differential effects of paced versus unpaced mating on anxiety and central oxytocin release in female rats.
      )
       Fear conditioning
      OXT 1 μg; icvMale Wistar ratsBefore cued-fear acquisition: decreased fear expression; before extinction training: impaired extinction(
      • Toth I.
      • Neumann I.D.
      • Slattery D.A.
      Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner.
      )
      OXT .1 μg; icvMale CD1 miceBefore extinction training: impaired extinction(
      • Toth I.
      • Neumann I.D.
      • Slattery D.A.
      Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner.
      )
      OXT .1 μg; icvMale CD1 miceBefore social fear extinction: abolished social fear expression(
      • Zoicas I.
      • Slattery D.A.
      • Neumann I.D.
      Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum.
      )
      OXT .01 μg; basolateral amygdalaMale Sprague Dawley ratsBefore contextual fear conditioning: enhanced fear expression and impaired extinction(
      • Lahoud N.
      • Maroun M.
      Oxytocinergic manipulations in corticolimbic circuit differentially affect fear acquisition and extinction.
      )
      WAY-267464 3 μg; TGOT 7 ng; central amygdalaMale Sprague Dawley ratsBefore contextual fear conditioning: reduced fear expression(
      • Lahoud N.
      • Maroun M.
      Oxytocinergic manipulations in corticolimbic circuit differentially affect fear acquisition and extinction.
      )
      OXT optogenetically evoked release; central amygdalaFemale Wistar ratsBefore retrieval: attenuated contextual fear expression(
      • Knobloch H.S.
      • Charlet A.
      • Hoffmann L.C.
      • Eliava M.
      • Khrulev S.
      • Cetin A.H.
      • et al.
      Evoked axonal oxytocin release in the central amygdala attenuates fear response.
      )
      TGOT 7 ng; central amygdalaBefore retrieval: attenuated contextual fear expression(
      • Viviani D.
      • Charlet A.
      • van den Burg E.
      • Robinet C.
      • Hurni N.
      • Abatis M.
      • et al.
      Oxytocin selectively gates fear responses through distinct outputs from the central amygdala.
      )
      OXT .01 μg; infralimbic cortexMale Sprague Dawley ratsFollowing contextual fear retrieval: facilitated subsequent extinction(
      • Lahoud N.
      • Maroun M.
      Oxytocinergic manipulations in corticolimbic circuit differentially affect fear acquisition and extinction.
      )
      TGOT 7 ng; central amygdalaMale Sprague Dawley ratsAttenuated contextual fear expression(
      • Viviani D.
      • Charlet A.
      • van den Burg E.
      • Robinet C.
      • Hurni N.
      • Abatis M.
      • et al.
      Oxytocin selectively gates fear responses through distinct outputs from the central amygdala.
      )
      OXT .01 μg; infralimbic cortexMale Sprague Dawley ratsFollowing contextual fear retrieval: facilitated subsequent extinction(
      • Lahoud N.
      • Maroun M.
      Oxytocinergic manipulations in corticolimbic circuit differentially affect fear acquisition and extinction.
      )
      OXT .01 μg; infralimbic cortexMale Sprague Dawley ratsFollowing contextual fear retrieval: facilitated subsequent extinction(
      • Lahoud N.
      • Maroun M.
      Oxytocinergic manipulations in corticolimbic circuit differentially affect fear acquisition and extinction.
      )
      OXT; dorsolateral septumMale CD1 miceBefore social fear extinction: abolished social fear expression(
      • Zoicas I.
      • Slattery D.A.
      • Neumann I.D.
      Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum.
      )
      OXT-R overexpression; lateral septumMale C57/BL6N miceEnhanced social defeat-induced contextual fear expression(
      • Guzman Y.F.
      • Tronson N.C.
      • Jovasevic V.
      • Sato K.
      • Guedea A.L.
      • Mizukami H.
      • et al.
      Fear-enhancing effects of septal oxytocin receptors.
      )
      OXT-R antagonist .75 μg; icvMale Wistar ratsBefore cued-fear acquisition: impaired fear extinction; no effect before extinction training(
      • Toth I.
      • Neumann I.D.
      • Slattery D.A.
      Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner.
      )
      Chronic/Repeated Studies
       OXT .08–8 IU/kg, 21 days; inMale prairie volesNo effect in EPM(
      • Bales K.L.
      • Perkeybile A.M.
      • Conley O.G.
      • Lee M.H.
      • Guoynes C.D.
      • Downing G.M.
      • et al.
      Chronic intranasal oxytocin causes long-term impairments in partner preference formation in male prairie voles.
      )
       OXT .8 IU/kg, 8 days; inMale and female C57BL/6J and BTBR miceNo effect in OF(
      • Bales K.L.
      • Solomon M.
      • Jacob S.
      • Crawley J.N.
      • Silverman J.L.
      • Larke R.H.
      • et al.
      Long-term exposure to intranasal oxytocin in a mouse autism model.
      )
       OXT 20 ng/hour, 7 days; icvMale Wistar ratsNo effect in OF or EPM(
      • Havranek T.
      • Zatkova M.
      • Lestanova Z.
      • Bacova Z.
      • Mravec B.
      • Hodosy J.
      • et al.
      Intracerebroventricular oxytocin administration in rats enhances object recognition and increases expression of neurotrophins, microtubule-associated protein 2, and synapsin I. J.
      )
       OXT 10–100 ng/hour, 5 days; icvFemale Sprague Dawley ratsAnxiolytic; EPM(
      • Windle R.J.
      • Shanks N.
      • Lightman S.L.
      • Ingram C.D.
      Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats.
      )
       OXT 1 and 10 ng/hour, 15 days; icvMale C57BL/6 miceAnxiogenic; 10 ng/hour on LDB and EPM(
      • Peters S.
      • Slattery D.A.
      • Uschold-Schmidt N.
      • Reber S.O.
      • Neumann I.D.
      Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice.
      )
       OXT 1 ng/hour, 19 days; icvMale C57BL/6Prevention of chronic stress-induced anxiogenesis; no effect in nonstressed mice(
      • Peters S.
      • Slattery D.A.
      • Uschold-Schmidt N.
      • Reber S.O.
      • Neumann I.D.
      Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice.
      )
       OXT 10 ng/hour, 6 days; icvMale and female HAB ratsAnxiolytic; LDB in female rats(
      • Slattery D.A.
      • Neumann I.D.
      Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats.
      )
       Carbetocin 10–100 μg, 10 days; icvMale Sprague Dawley ratsAnxiolytic; 32 and 100 μg on EPM(
      • Mak P.
      • Broussard C.
      • Vacy K.
      • Broadbear J.H.
      Modulation of anxiety behavior in the elevated plus maze using peptidic oxytocin and vasopressin receptor ligands in the rat.
      )
       OXT-R antagonist 7.5 ng/hour, 6 days; icvMale and female LAB ratsAnxiogenic effect; LDB in female rats(
      • Slattery D.A.
      • Neumann I.D.
      Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats.
      )
       Oxytocin knockout miceFemale 129 MiceHigher anxiety in knockouts; EPM(
      • Amico J.A.
      • Mantella R.C.
      • Vollmer R.R.
      • Li X.
      Anxiety and stress responses in female oxytocin deficient mice.
      )
      EPM, elevated plus maze; EZM, elevated zero maze; FPT, four plate test; HAB, high anxiety-related behavior; icv, intracerebroventricular; in, intranasal; ip, intraperitoneal; LAB, low anxiety-related behavior; LDB, light-dark box; OF, open-field; OXT, oxytocin; OXT-R, oxytocin receptor; PVN, paraventricular; SIH, stress-induced hyperthermia.
      We have also shown that the robust anxiolytic activity of OXT in the PVN depends on the sequential activation of several OXT-R-mediated intraneuronal signaling pathways. Specifically, local infusion of OXT results in activation of the mitogen-activated protein kinase pathway (
      • Blume A.
      • Bosch O.J.
      • Miklos S.
      • Torner L.
      • Wales L.
      • Waldherr M.
      • Neumann I.D.
      Oxytocin reduces anxiety via ERK1/2 activation: Local effect within the rat hypothalamic paraventricular nucleus.
      ,
      • Jurek B.
      • Slattery D.A.
      • Maloumby R.
      • Hillerer K.
      • Koszinowski S.
      • Neumann I.D.
      • van den Burg E.H.
      Differential contribution of hypothalamic MAPK activity to anxiety-like behaviour in virgin and lactating rats.
      ), and blockade of this pathway prevents the local anxiolytic effects of OXT. Interestingly, in the peripartum period, both the OXT system and the OXT-R-driven mitogen-activated protein kinase pathway are highly activated within the PVN, even in the absence of synthetic OXT (
      • Jurek B.
      • Slattery D.A.
      • Maloumby R.
      • Hillerer K.
      • Koszinowski S.
      • Neumann I.D.
      • van den Burg E.H.
      Differential contribution of hypothalamic MAPK activity to anxiety-like behaviour in virgin and lactating rats.
      ). Blockade of the signaling pathway also prevents the anxiolytic state of lactating rats. Additionally, we could recently identify that increased intracellular calcium levels via insertion of transient receptor potential vanilloid (TRPV) channels into the membrane also mediates the acute anxiolytic effect of OXT in the PVN (
      • van den Burg E.H.
      • Stindl J.
      • Grund T.
      • Neumann I.D.
      • Strauss O.
      Oxytocin stimulates extracellular Ca2+ influx through TRPV2 channels in hypothalamic neurons to exert its anxiolytic effects.
      ).

      Chronic Effects of Synthetic OXT on Anxiety

      When considering OXT as an anxiolytic treatment option for humans, chronic neuropeptide effects should be of major interest. 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 (
      • Slattery D.A.
      • Neumann I.D.
      Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats.
      ,
      • Windle R.J.
      • Kershaw Y.M.
      • Shanks N.
      • Wood S.A.
      • Lightman S.L.
      • Ingram C.D.
      Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity.
      ,
      • Peters S.
      • Slattery D.A.
      • Uschold-Schmidt N.
      • Reber S.O.
      • Neumann I.D.
      Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice.
      ,
      • Huang H.
      • Michetti C.
      • Busnelli M.
      • Manago F.
      • Sannino S.
      • Scheggia D.
      • et al.
      Chronic and acute intranasal oxytocin produce divergent social effects in mice.
      ,
      • Havranek T.
      • Zatkova M.
      • Lestanova Z.
      • Bacova Z.
      • Mravec B.
      • Hodosy J.
      • et al.
      Intracerebroventricular oxytocin administration in rats enhances object recognition and increases expression of neurotrophins, microtubule-associated protein 2, and synapsin I. J.
      ,
      • Bales K.L.
      • Perkeybile A.M.
      • Conley O.G.
      • Lee M.H.
      • Guoynes C.D.
      • Downing G.M.
      • et al.
      Chronic intranasal oxytocin causes long-term impairments in partner preference formation in male prairie voles.
      ,
      • Bales K.L.
      • Solomon M.
      • Jacob S.
      • Crawley J.N.
      • Silverman J.L.
      • Larke R.H.
      • et al.
      Long-term exposure to intranasal oxytocin in a mouse autism model.
      ,
      • Windle R.J.
      • Shanks N.
      • Lightman S.L.
      • Ingram C.D.
      Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats.
      ), and are dependent upon the innate level of anxiety (
      • Slattery D.A.
      • Neumann I.D.
      Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats.
      ). 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 (
      • Peters S.
      • Slattery D.A.
      • Uschold-Schmidt N.
      • Reber S.O.
      • Neumann I.D.
      Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice.
      ). 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 (
      • Windle R.J.
      • Kershaw Y.M.
      • Shanks N.
      • Wood S.A.
      • Lightman S.L.
      • Ingram C.D.
      Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity.
      ,
      • Windle R.J.
      • Shanks N.
      • Lightman S.L.
      • Ingram C.D.
      Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats.
      ). In support of such sex differences, 7 days icv OXT (20 ng/hour) in male rats did not affect anxiety-related behavior (
      • Havranek T.
      • Zatkova M.
      • Lestanova Z.
      • Bacova Z.
      • Mravec B.
      • Hodosy J.
      • et al.
      Intracerebroventricular oxytocin administration in rats enhances object recognition and increases expression of neurotrophins, microtubule-associated protein 2, and synapsin I. J.
      ).
      To further test for the potential therapeutic value of OXT in the context of anxiety disorders, we proved its efficacy in rats selectively bred for high anxiety-related behavior (HAB) versus low anxiety-related behavior (LAB) (
      • Frank E.
      • Landgraf R.
      The vasopressin system--from antidiuresis to psychopathology.
      ,
      • Landgraf R.
      • Wigger A.
      Born to be anxious: Neuroendocrine and genetic correlates of trait anxiety in HAB rats.
      ). Interestingly, we only found an anxiolytic effect of OXT in female, but not male, HAB rats after chronic, but not acute, icv application. In contrast, LAB females administered chronic OXT-R antagonist showed increased anxiety-related behavior, which provides further indication for a role of the endogenous OXT system in the anxiety phenotype of HAB and LAB female rats (
      • Slattery D.A.
      • Neumann I.D.
      Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats.
      ). The relatively low effectiveness of OXT to modulate extreme anxiety levels in these animals is likely due to their rigid genetic predisposition toward the selected behavioral trait, namely anxiety.
      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) (
      • Peters S.
      • Slattery D.A.
      • Uschold-Schmidt N.
      • Reber S.O.
      • Neumann I.D.
      Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice.
      ,
      • Huang H.
      • Michetti C.
      • Busnelli M.
      • Manago F.
      • Sannino S.
      • Scheggia D.
      • et al.
      Chronic and acute intranasal oxytocin produce divergent social effects in mice.
      ). 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 (
      • Conti F.
      • Sertic S.
      • Reversi A.
      • Chini B.
      Intracellular trafficking of the human oxytocin receptor: Evidence of receptor recycling via a Rab4/Rab5 "short cycle".
      ). Interestingly, after chronic OXT treatment, AVP receptor binding was found to be increased in the lateral septum (
      • Huang H.
      • Michetti C.
      • Busnelli M.
      • Manago F.
      • Sannino S.
      • Scheggia D.
      • et al.
      Chronic and acute intranasal oxytocin produce divergent social effects in mice.
      ), where AVP exerts robust anxiogenic effects (
      • Landgraf R.
      • Gerstberger R.
      • Montkowski A.
      • Probst J.C.
      • Wotjak C.T.
      • Holsboer F.
      • Engelmann M.
      V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats.
      ). In this context, it is worth mentioning that OXT can bind to AVP receptors (and vice versa) (
      • Chini B.
      • Manning M.
      Agonist selectivity in the oxytocin/vasopressin receptor family: New insights and challenges.
      ), but to what extent chronic alterations in OXT or OXT-R availability directly affect AVP receptor expression remains unknown at present.
      Taken together, these studies highlight potential species and sex differences in the response to chronic OXT (for summary see Table 1). Without any doubt, we have to expect similar undesired counterregulatory consequences after chronic or repeated intranasal OXT application in humans, and more detailed basic studies are essentially needed.

      Oxt and General Anxiety: Human Research

      Human researchers have suggested a possible relationship between peripheral OXT levels, OXT-R gene polymorphisms, and GAD. In detail, basal plasma OXT concentrations were found to depend upon the mental health state and gender of the test person. For example, a positive relationship between (basal) plasma OXT and state anxiety has been reported in women (
      • Holt-Lunstad J.
      • Birmingham W.
      • Light K.C.
      The influence of depressive symptomatology and perceived stress on plasma and salivary oxytocin before, during and after a support enhancement intervention.
      ,
      • Tops M.
      • van Peer J.M.
      • Korf J.
      • Wijers A.A.
      • Tucker D.M.
      Anxiety, cortisol, and attachment predict plasma oxytocin.
      ), whereas plasma (and cerebrospinal fluid) OXT concentrations negatively predicted trait anxiety scores in a mixed-gender cohort (11 male and 16 female subjects) of child and adult patients (
      • Carson D.S.
      • Berquist S.W.
      • Trujillo T.H.
      • Garner J.P.
      • Hannah S.L.
      • Hyde S.A.
      • et al.
      Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children.
      ) and in male, but not female, subjects in another study (
      • Weisman O.
      • Zagoory-Sharon O.
      • Schneiderman I.
      • Gordon I.
      • Feldman R.
      Plasma oxytocin distributions in a large cohort of women and men and their gender-specific associations with anxiety.
      ). Moreover, associations between OXT-R polymorphisms and anxiety were described with two single nucleotide polymorphisms (SNPs), rs53576 and rs2254298, found to be associated with separation anxiety in depressed patients (
      • Costa B.
      • Pini S.
      • Gabelloni P.
      • Abelli M.
      • Lari L.
      • Cardini A.
      • et al.
      Oxytocin receptor polymorphisms and adult attachment style in patients with depression.
      ) and to interact with the level of anxiety symptoms in adolescent girls (
      • Thompson R.J.
      • Parker K.J.
      • Hallmayer J.F.
      • Waugh C.E.
      • Gotlib I.H.
      Oxytocin receptor gene polymorphism (rs2254298) interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls.
      ). Similarly, in a large study assessing multiple OXT-R polymorphisms, an interaction between retrospectively assessed early-life stress exposure and OXT-R genotype on self-reported anxiety symptoms was found (
      • Myers A.J.
      • Williams L.
      • Gatt J.M.
      • McAuley-Clark E.Z.
      • Dobson-Stone C.
      • Schofield P.R.
      • Nemeroff C.B.
      Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress.
      ). However, the functional implications of these SNPs on the OXT system remain to be shown.
      There have been surprisingly few attempts to investigate whether intranasal OXT has anxiolytic properties in GAD patients (
      • Feifel D.
      • MacDonald K.
      • McKinney R.
      • Heisserer N.
      • Serrano V.
      A randomized, placebo-controlled investigation of intranasal oxytocin in patients with anxiety.
      ) [see (
      • MacDonald K.
      • Feifel D.
      Oxytocin’s role in anxiety: A critical appraisal.
      ) for review]. This one study supports a beneficial effect of daily OXT administration in GAD patients over 3 weeks, especially in male subjects (
      • Myers A.J.
      • Williams L.
      • Gatt J.M.
      • McAuley-Clark E.Z.
      • Dobson-Stone C.
      • Schofield P.R.
      • Nemeroff C.B.
      Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress.
      ). In the context of human anxiety, the majority of studies have been performed in volunteers in variants of the Trier Social Stress Test, which, on the whole, revealed that acute intranasal OXT reduces anxiety symptoms (
      • Alvares G.A.
      • Chen N.T.
      • Balleine B.W.
      • Hickie I.B.
      • Guastella A.J.
      Oxytocin selectively moderates negative cognitive appraisals in high trait anxious males.
      ,
      • de Oliveira D.C.
      • Zuardi A.W.
      • Graeff F.G.
      • Queiroz R.H.
      • Crippa J.A.
      Anxiolytic-like effect of oxytocin in the simulated public speaking test.
      ,
      • Goodin B.R.
      • Anderson A.J.
      • Freeman E.L.
      • Bulls H.W.
      • Robbins M.T.
      • Ness T.J.
      Intranasal oxytocin administration is associated with enhanced endogenous pain inhibition and reduced negative mood states [published online ahead of print November 3].
      ,
      • Heinrichs M.
      • Baumgartner T.
      • Kirschbaum C.
      • Ehlert U.
      Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress.
      ,
      • Pierrehumbert B.
      • Torrisi R.
      • Laufer D.
      • Halfon O.
      • Ansermet F.
      • Beck Popovic M.
      Oxytocin response to an experimental psychosocial challenge in adults exposed to traumatic experiences during childhood or adolescence.
      ). However, it is clear that further studies assessing the effect of chronic or repeated OXT administration, and in GAD patients, are warranted.

      The Balanced Activity of The Brain Oxt System In General Anxiety Regulation

      Regarding the role of OXT in animal and human anxiety regulation, we have previously hypothesized that the balanced activity of brain OXT (and AVP) systems importantly impacts on emotional (and social) behaviors along a continuum reaching from mental health up to psychopathology (
      • Neumann I.D.
      • Landgraf R.
      Balance of brain oxytocin and vasopressin: Implications for anxiety, depression, and social behaviors.
      ) (Figure 1). For example, low brain OXT activity, hypothesized to be associated with high anxiety levels, can be reflected by 1) low hypothalamic OXT gene expression, 2) low levels of central OXT release and OXT availability in the local extracellular fluid under basal and/or stimulated conditions, and/or 3) low OXT-R expression and binding in brain regions relevant for emotional and social behaviors. These parameters can be shifted towards the right (Figure 1) by physiological (e.g., lactation, sexual activity) and environmental (e.g., positive social interactions) stimuli and are likely determined by genetic and epigenetic factors. Moreover, increasing the availability of OXT in the brain extracellular fluid, possibly in combination with psychopharmacotherapy, may also result in a shift of OXT activity toward the right (Figure 1). Indeed, factors that acutely increase the activity of the OXT system have been shown to reduce state anxiety and to promote prosocial behaviors (see below). However, an adaptive shift of the brain OXT system toward the left, for example, in chronic adverse life environments, might be important to ensure evolutionary beneficial anxiety levels.
      Figure thumbnail gr1
      Figure 1The activity of the brain oxytocin (OXT) system is mainly reflected by the level of expression of OXT or its receptor, by local OXT release into and local OXT availability within the extracellular fluid, and by the OXT receptor binding capacity. Genetic and epigenetic factors, physiological conditions, such as reproduction or stress, as well as environmental and social stimuli significantly contribute to the individual expression and modulation of these parameters. Further, combined psychopharmacotherapy with the aim to increase central oxytocin availability may shift the activity of the oxytocin system toward the right, which is likely to be accompanied by reduced anxiety and improved social competence. For details, see text. [Adapted from Neumann and Landgraf (
      • Neumann I.D.
      • Landgraf R.
      Balance of brain oxytocin and vasopressin: Implications for anxiety, depression, and social behaviors.
      )].

      Oxt and Cued Fear Conditioning As A Rodent Model of Posttraumatic Stress Disorder

      Inability to extinguish fear memories is a core symptom in several psychiatric disorders, such as PTSD, SAD, and panic disorder, and has been linked to hyperactivity of the amygdala (
      • Shin L.M.
      • Orr S.P.
      • Carson M.A.
      • Rauch S.L.
      • Macklin M.L.
      • Lasko N.B.
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      Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD.
      ,
      • Williams L.M.
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      Trauma modulates amygdala and medial prefrontal responses to consciously attended fear.
      ). Cued fear conditioning has been used in laboratory animals as a model of PTSD and involves pairing a neutral stimulus (tone or light as conditioned stimulus) with an aversive, unconditioned stimulus, such as a mild foot shock, thereby eliciting a freezing response to the previously neutral stimulus (
      • Orsini C.A.
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      Neural and cellular mechanisms of fear and extinction memory formation.
      ,
      • Singewald N.
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      Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders.
      ). During fear extinction performed 24 hours later and repeated exposure to the conditioned stimulus only, the conditioned response should be attenuated via processes of relearning (
      • Cammarota M.
      • Bevilaqua L.R.
      • Vianna M.R.
      • Medina J.H.
      • Izquierdo I.
      The extinction of conditioned fear: Structural and molecular basis and therapeutic use.
      ,
      • Quirk G.J.
      • Pare D.
      • Richardson R.
      • Herry C.
      • Monfils M.H.
      • Schiller D.
      • Vicentic A.
      Erasing fear memories with extinction training.
      ).
      Initial studies revealing distinct and differential c-Fos activation of OXT neurons following various phases of fear conditioning supported a role for the endogenous OXT system in fear acquisition and extinction (
      • Zhu L.
      • Onaka T.
      Involvement of medullary A2 noradrenergic neurons in the activation of oxytocin neurons after conditioned fear stimuli.
      ). Thereafter, studies revealed that, as with other systems that affect fear learning, the timing and location of OXT administration critically determine its outcome. Thus, we could demonstrate in male rats that icv OXT before acquisition of cued fear conditioning did not affect cued fear acquisition, as OXT-infused rats learned the association between the conditioned and unconditioned stimulus to the same degree as control rats. In contrast, the same treatment decreased fear expression 24 hours later. In confirmation of a substantial role of brain OXT in fear consolidation, icv administration of an OXT-R antagonist at the same time impaired fear extinction. Surprisingly, when applied 10 minutes before fear extinction training, icv OXT impaired, whereas the OXT-R antagonist facilitated, cued fear extinction (
      • Toth I.
      • Neumann I.D.
      • Slattery D.A.
      Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner.
      ). Moreover, the effects of OXT on fear expression and extinction appear to be region specific. Infusion of OXT into the basolateral amygdala of male rats before contextual fear conditioning led to enhanced fear expression and impaired extinction, whereas infusion of either WAY-267464 or TGOT (both OXT agonists) into the central amygdala before fear conditioning reduced fear expression (
      • Lahoud N.
      • Maroun M.
      Oxytocinergic manipulations in corticolimbic circuit differentially affect fear acquisition and extinction.
      ). In an elegant study, optogenetically stimulated local release of OXT as well as synthetic OXT infusion in the central amygdala of rats before contextual fear extinction reduced fear expression by reducing the output of the centromedial amygdala in response to the conditioned stimulus (
      • Knobloch H.S.
      • Charlet A.
      • Hoffmann L.C.
      • Eliava M.
      • Khrulev S.
      • Cetin A.H.
      • et al.
      Evoked axonal oxytocin release in the central amygdala attenuates fear response.
      ,
      • Huber D.
      • Veinante P.
      • Stoop R.
      Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala.
      ,
      • Viviani D.
      • Charlet A.
      • van den Burg E.
      • Robinet C.
      • Hurni N.
      • Abatis M.
      • et al.
      Oxytocin selectively gates fear responses through distinct outputs from the central amygdala.
      ).
      Taken together, these studies support a role of the endogenous OXT system in the acquisition and extinction of fear, and this appears to be time- and region-dependent (for summary see Table 1). Moreover, these temporally- and spatially-dependent effects of OXT on fear extinction clearly extend our model of the balanced brain OXT system (Figure 1) and indicate an adaptive role of OXT in fear conditioning. A generally high OXT activity at the time of acquisition, due to either endogenous factors or pharmacologic manipulation, is likely to be associated with lower fear expression. However, once cued fear has consolidated, an acute high OXT may rather impair fear extinction.
      Also, these findings have to be carefully considered and extended before using OXT for the treatment of PTSD caused by nonsocial traumatic events. However, as we will see further in the text, OXT seems to be particularly effective only in a social context.

      Oxt Effects On Social Behavior: from Social Preference To Social Fear

      The prosocial effects of OXT are extensively summarized elsewhere (
      • Meyer-Lindenberg A.
      • Domes G.
      • Kirsch P.
      • Heinrichs M.
      Oxytocin and vasopressin in the human brain: Social neuropeptides for translational medicine.
      ,
      • Heinrichs M.
      • Baumgartner T.
      • Kirschbaum C.
      • Ehlert U.
      Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress.
      ,
      • Neumann I.D.
      The advantage of social living: Brain neuropeptides mediate the beneficial consequences of sex and motherhood.
      ,
      • Donaldson Z.R.
      • Young L.J.
      Oxytocin, vasopressin, and the neurogenetics of sociality.
      ,
      • Lukas M.
      • Neumann I.D.
      Oxytocin and vasopressin in rodent behaviors related to social dysfunctions in autism spectrum disorders.
      ), but in this context, it is worth mentioning that brain OXT is essential for naturally occurring social preference behavior in rats and mice as analyzed in the social preference-avoidance test (
      • Toth I.
      • Neumann I.D.
      Animal models of social avoidance and social fear.
      ,
      • Lukas M.
      • Toth I.
      • Reber S.O.
      • Slattery D.A.
      • Veenema A.H.
      • Neumann I.D.
      The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice.
      ). In detail, OXT was found to be released within the lateral septum during social interaction and investigation of conspecifics (
      • Zoicas I.
      • Slattery D.A.
      • Neumann I.D.
      Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum.
      ). Blockade of central receptor-mediated OXT actions by icv infusion of an OXT-R antagonist prevented social preference behavior in rodents (
      • Lukas M.
      • Toth I.
      • Reber S.O.
      • Slattery D.A.
      • Veenema A.H.
      • Neumann I.D.
      The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice.
      ). Moreover, exposure to 30 minutes of social defeat by a slightly larger male resident rat before the social preference test induced an avoidance of the conspecific, which could be acutely reversed by icv infusion of OXT. These observations together with the findings that OXT knockout mice display impaired social behaviors (
      • Crawley J.N.
      • Chen T.
      • Puri A.
      • Washburn R.
      • Sullivan T.L.
      • Hill J.M.
      • et al.
      Social approach behaviors in oxytocin knockout mice: Comparison of two independent lines tested in different laboratory environments.
      ) support the hypothesis that high levels of brain OXT activity generally promote naturally-occurring social preference and social competence (Figure 1). Although further, and especially more long-lasting, studies are needed, the possibility emerged of OXT being a treatment option for social dysfunctions and, specifically, for social fear (
      • Lukas M.
      • Toth I.
      • Reber S.O.
      • Slattery D.A.
      • Veenema A.H.
      • Neumann I.D.
      The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice.
      ).
      However, social defeat can result in a variety of other symptoms that may influence social anxiety. Therefore, to more specifically study the role of OXT in social fear, we have recently established an operant social fear conditioning paradigm in mice, where conditioned mice receive a footshock when actively investigating a conspecific (
      • Toth I.
      • Neumann I.D.
      Animal models of social avoidance and social fear.
      ,
      • Toth I.
      • Neumann I.D.
      • Slattery D.A.
      Social fear conditioning as an animal model of social anxiety disorder.
      ,
      • Toth I.
      • Neumann I.D.
      • Slattery D.A.
      Social fear conditioning: A novel and specific animal model to study social anxiety disorder.
      ). As a result, social fear conditioning specifically induces social fear toward unknown conspecifics, which is expressed as decreased social investigation and aversive responses toward conspecifics in the experimental animal’s home cage. Moreover, as occurs in SAD (and PTSD), this fear sensitizes over time and lasts for at least 2 weeks. During fear extinction training, repeated exposure to social stimuli without punishment gradually reinstates social preference behavior, i.e., loss of social fear (
      • Toth I.
      • Neumann I.D.
      Animal models of social avoidance and social fear.
      ,
      • Toth I.
      • Neumann I.D.
      • Slattery D.A.
      Social fear conditioning as an animal model of social anxiety disorder.
      ,
      • Toth I.
      • Neumann I.D.
      • Slattery D.A.
      Social fear conditioning: A novel and specific animal model to study social anxiety disorder.
      ).
      Social fear could be associated with profound changes in the brain OXT system, as it specifically resulted in elevated OXT-R binding in regions associated with the fear circuitry, including the dorsolateral septum, central amygdala, hippocampus, and the median raphe nucleus (
      • Zoicas I.
      • Slattery D.A.
      • Neumann I.D.
      Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum.
      ). The alterations in OXT-R binding were found to be reversed after social fear extinction. In support of our findings of elevated OXT-R binding in socially fearful mice are the observations that 1) OXT-R expression is locally elevated in chronically defeated mice, which also showed signs of social avoidance (
      • Litvin Y.
      • Murakami G.
      • Pfaff D.W.
      Effects of chronic social defeat on behavioral and neural correlates of sociality: Vasopressin, oxytocin and the vasopressinergic V1b receptor.
      ); and 2) virus-induced overexpression of the OXT-R within the septum increased contextual fear expression (
      • Guzman Y.F.
      • Tronson N.C.
      • Jovasevic V.
      • Sato K.
      • Guedea A.L.
      • Mizukami H.
      • et al.
      Fear-enhancing effects of septal oxytocin receptors.
      ). It is likely that these observed changes in OXT-R binding are directly due to reduced local OXT release and availability, as OXT release within the dorsolateral septum during exploration of a conspecific—strongly increased in unconditioned mice—was indeed blunted in social fear conditioning mice. In support, both icv and intraseptal OXT infusion before extinction training abolished fear expression (
      • Zoicas I.
      • Slattery D.A.
      • Neumann I.D.
      Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum.
      ). The findings that OXT strongly facilitates extinction of social fear, in contrast to the differential effects on cued fear extinction, suggest that either the circuitry involved in social fear differs from that of cued fear (see above) or that the combined prosocial and anxiolytic properties of OXT are sufficient to overcome social fear. Thus, increasing brain OXT activity toward the right, for example, by intracerebral infusion of synthetic OXT, and consequently increasing OXT availability in the local extracellular fluid (Figure 1) is associated with the attenuation or even reversal of social fear. To what extent stimulation of the endogenous OXT system may also be beneficial in this context needs to be shown.

      Oxt In Ptsd and Social Anxiety Disorder: Human Research

      Numerous human studies have reported on the OXT system in relation to both PTSD and SAD. In one of the first reports assessing intranasal OXT in Vietnam veterans with PTSD, no beneficial effects on physiological responses to combat imagery were observed (
      • Pitman R.K.
      • Orr S.P.
      • Lasko N.B.
      Effects of intranasal vasopressin and oxytocin on physiologic responding during personal combat imagery in Vietnam veterans with posttraumatic stress disorder.
      ). However, more recent studies support a beneficial role for intranasal OXT in healthy volunteers exposed to a conditioning/extinction paradigm with respect to the bodily response and reduction of amygdala activity throughout extinction (
      • Eckstein M.
      • Becker B.
      • Scheele D.
      • Scholz C.
      • Preckel K.
      • Schlaepfer T.E.
      • et al.
      Oxytocin facilitates the extinction of conditioned fear in humans.
      ,
      • Acheson D.
      • Feifel D.
      • de Wilde S.
      • McKinney R.
      • Lohr J.
      • Risbrough V.
      The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample.
      ). In contrast, intranasal OXT increased the startle response to unpredictable shocks (
      • Grillon C.
      • Krimsky M.
      • Charney D.R.
      • Vytal K.
      • Ernst M.
      • Cornwell B.
      Oxytocin increases anxiety to unpredictable threat.
      ). Thus, in addition to the temporal and spatial differences of OXT on fear extinction reported above, the nature of the threat (social vs. nonsocial, predictable vs. unpredictable traumatic events) also appears to play an important role in the effectiveness of synthetic OXT in humans.
      Various studies performed in SAD patients have assessed plasma OXT levels, OXT-R gene methylation and SNPs, and the effect of intranasal OXT on SAD symptoms. The reports relating to plasma OXT and SAD have been inconsistent and need to be interpreted with caution due, partly, to invalid assay methods (see above). Moreover, reduced OXT-R methylation in SAD patients was associated with symptom severity, elevated stress-induced cortisol responses, and increased amygdala activity (
      • Ziegler C.
      • Dannlowski U.
      • Brauer D.
      • Stevens S.
      • Laeger I.
      • Wittmann H.
      • et al.
      Oxytocin receptor gene methylation: Converging multilevel evidence for a role in social anxiety.
      ). Since decreased methylation is likely to result in increased OXT-R expression, these findings support our results in socially fearful mice (
      • Zoicas I.
      • Slattery D.A.
      • Neumann I.D.
      Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum.
      ). Thus, increased OXT-R expression possibly due to low local OXT release may represent a conserved mechanism whereby the memory of adverse social events is maintained leading to social anxiety.
      Intranasal OXT given either alone or in combination with exposure therapy has generally led to positive results in SAD in terms of positive self-evaluation of public performance (
      • Guastella A.J.
      • Howard A.L.
      • Dadds M.R.
      • Mitchell P.
      • Carson D.S.
      A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder.
      ) and regional neuronal activity patterns and amygdala-prefrontal connectivity in response to emotional faces (
      • Dodhia S.
      • Hosanagar A.
      • Fitzgerald D.A.
      • Labuschagne I.
      • Wood A.G.
      • Nathan P.J.
      • Phan K.L.
      Modulation of resting-state amygdala-frontal functional connectivity by oxytocin in generalized social anxiety disorder.
      ,
      • Gorka S.M.
      • Fitzgerald D.A.
      • Labuschagne I.
      • Hosanagar A.
      • Wood A.G.
      • Nathan P.J.
      • Phan K.L.
      Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder.
      ,
      • Labuschagne I.
      • Phan K.L.
      • Wood A.
      • Angstadt M.
      • Chua P.
      • Heinrichs M.
      • et al.
      Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder.
      ). Also, in fragile X patients, who also display symptoms of social anxiety, intranasal OXT improved eye gazing and reduced cortisol response to a social challenge (
      • Hall S.S.
      • Lightbody A.A.
      • McCarthy B.E.
      • Parker K.J.
      • Reiss A.L.
      Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome.
      ).

      Summary

      In summary, there is profound evidence for an important role of the OXT system in general anxiety and social fear, in addition to its many prosocial effects. Differing activities of the brain OXT system, including gene expression patterns and local release, which are determined by genetic and epigenetic factors, are likely to underlie differences in emotional and social behaviors. High central OXT availability, for example, seems to be associated with an anxiolytic and prosocial, socially competent phenotype. In contrast, a gradual shift of the activity scale toward the left, e.g., by diminished OXT–OXT-R interactions, is associated with elevated nonsocial anxiety, lack of social preference, and social fear. However, before the OXT system can be considered a safe treatment target, various molecular, neuronal, and brain network variables need to be studied in more detail after acute, repeated, or chronic OXT application in animal and human studies. Moreover, biological markers of the activity and responsiveness of the endogenous OXT system (Figure 1) need to be validated and employed to distinguish potential OXT responders and nonresponders to avoid disadvantageous effects in the latter.

      Acknowledgments and Disclosures

      This work was supported by the European Research Council, Bundesministerium für Bildung und Forschung, Elitenetwork of Bavaria (IDN), and the Deutsche Forschungsgemeinschaft (IDN, DAS).
      The authors report no biomedical financial interests or potential conflicts of interest.

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