Advertisement

Oxytocin Facilitates the Extinction of Conditioned Fear in Humans

      Abstract

      Background

      Current neurocircuitry models of anxiety disorders posit a lack of inhibitory tone in the amygdala during acquisition of Pavlovian fear responses and deficient encoding of extinction responses in amygdala–medial prefrontal cortex circuits. Competition between these two responses often results in a return of fear, limiting control over anxiety. However, one hypothesis holds that a pharmacologic strategy aimed at reducing amygdala activity while simultaneously augmenting medial prefrontal cortex function could facilitate the extinction of conditioned fear.

      Methods

      Key among the endogenous inhibitors of amygdala activity in response to social fear signals is the hypothalamic peptide oxytocin. To address the question whether oxytocin can strengthen Pavlovian extinction beyond its role in controlling social fear, we conducted a functional magnetic resonance imaging experiment with 62 healthy male participants in a randomized, double-blind, parallel-group, placebo-controlled design. Specifically, subjects were exposed to a Pavlovian fear conditioning paradigm before receiving an intranasal dose (24 IU) of synthetic oxytocin or placebo.

      Results

      Oxytocin, when administered intranasally after Pavlovian fear conditioning, was found to increase electrodermal responses and prefrontal cortex signals to conditioned fear in the early phase of extinction and to enhance the decline of skin conductance responses in the late phase of extinction. Oxytocin also evoked an unspecific inhibition of amygdalar responses in both phases.

      Conclusions

      Collectively, our findings identify oxytocin as a differentially acting modulator of neural hubs involved in Pavlovian extinction. This specific profile of oxytocin action may open up new avenues for enhancing extinction-based therapies for anxiety disorders.

      Keywords

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • McNally R.J.
        Mechanisms of exposure therapy: How neuroscience can improve psychological treatments for anxiety disorders.
        Clin Psychol Rev. 2007; 27: 750-759
        • Kessler R.C.
        • McGonagle K.A.
        • Zhao S.
        • Nelson C.B.
        • Hughes M.
        • Eshleman S.
        • et al.
        Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the united states: Results from the national comorbidity survey.
        Arch Gen Psychiatry. 1994; 51: 8-19
        • Hofmann S.G.
        Enhancing exposure-based therapy from a translational research perspective.
        Behav Res Ther. 2007; 45: 1987-2001
        • Bradley R.
        • Greene J.
        • Russ E.
        • Dutra L.
        • Westen D.
        A multidimensional meta-analysis of psychotherapy for PTSD.
        Am J Psychiatry. 2005; 162: 214-227
        • Cloitre M.
        Effective psychotherapies for posttraumatic stress disorder: A review and critique.
        CNS Spectr. 2009; 14: 32-43
        • Myers K.
        • Davis M.
        Mechanisms of fear extinction.
        Mol Psychiatry. 2007; 12: 120-150
        • Sehlmeyer C.
        • Schöning S.
        • Zwitserlood P.
        • Pfleiderer B.
        • Kircher T.
        • Arolt V.
        • et al.
        Human fear conditioning and extinction in neuroimaging: A systematic review.
        PloS One. 2009; 4: e5865
        • Hermans D.
        • Craske M.G.
        • Mineka S.
        • Lovibond P.F.
        Extinction in human fear conditioning.
        Biol Psychiatry. 2006; 60: 361-368
        • Milad M.R.
        • Quirk G.J.
        Fear extinction as a model for translational neuroscience: Ten years of progress.
        Ann Rev Psychol. 2012; 63: 129-151
        • Vouimba R.-M.
        • Maroun M.
        Learning-induced changes in mPFC-BLA connections after fear conditioning, extinction, and reinstatement of fear.
        Neuropsychopharmacology. 2011; 36: 2276-2285
        • Etkin A.
        • Wager T.
        Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.
        Am J Psychiatry. 2007; 164: 1476-1488
        • Goossens L.
        • Sunaert S.
        • Peeters R.
        • Griez E.J.
        • Schruers K.R.
        Amygdala hyperfunction in phobic fear normalizes after exposure.
        Biol Psychiatry. 2007; 62: 1119-1125
        • Rothbaum B.O.
        • Price M.
        • Jovanovic T.
        • Norrholm S.D.
        • Gerardi M.
        • Dunlop B.
        • et al.
        A randomized, double-blind evaluation of d-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan war veterans.
        Am J Psychiatry. 2014; 171: 640-648
        • Marsicano G.
        • Wotjak C.T.
        • Azad S.C.
        • Bisogno T.
        • Rammes G.
        • Cascio M.G.
        • et al.
        The endogenous cannabinoid system controls extinction of aversive memories.
        Nature. 2002; 418: 530-534
        • 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.
        Neuron. 2012; 73: 553-566
        • Striepens N.
        • Kendrick K.M.
        • Maier W.
        • Hurlemann R.
        Prosocial effects of oxytocin and clinical evidence for its therapeutic potential.
        Front Neuroendocrinol. 2011; 32: 426-450
        • Eckstein M.
        • Hurlemann R.
        Oxytozin.
        Nervenarzt. 2013; 84: 1321-1328
        • Gould B.
        • Zingg H.
        Mapping oxytocin receptor gene expression in the mouse brain and mammary gland using an oxytocin receptor–LacZ reporter mouse.
        Neuroscience. 2003; 122: 155-167
        • Boccia M.L.
        • Petrusz P.
        • Suzuki K.
        • Marson L.
        • Pedersen C.A.
        Immunohistochemical localization of oxytocin receptors in human brain.
        Neuroscience. 2013; 253: 155-164
        • Striepens N.
        • Scheele D.
        • Kendrick K.M.
        • Becker B.
        • Schafer L.
        • Schwalba K.
        • et al.
        Oxytocin facilitates protective responses to aversive social stimuli in males.
        Proc Natl Acad Sci U S A. 2012; 109: 18144-18149
        • Kirsch P.
        • Esslinger C.
        • Chen Q.
        • Mier D.
        • Lis S.
        • Siddhanti S.
        • et al.
        Oxytocin modulates neural circuitry for social cognition and fear in humans.
        J Neurosci. 2005; 25: 11489-11493
        • Domes G.
        • Heinrichs M.
        • Glascher J.
        • Buchel C.
        • Braus D.
        • Herpertz S.
        Oxytocin attenuates amygdala responses to emotional faces regardless of valence.
        Biol Psychiatry. 2007; 62: 1187-1190
        • Sripada C.S.
        • Phan K.L.
        • Labuschagne I.
        • Welsh R.
        • Nathan P.J.
        • Wood A.G.
        Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex.
        Int J Neuropsychopharmacol. 2013; 16: 255-260
        • Petrovic P.
        • Kalisch R.
        • Singer T.
        • Dolan R.
        Oxytocin attenuates affective evaluations of conditioned faces and amygdala activity.
        J Neurosci. 2008; 28: 6607-6615
        • 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.
        Psychopharmacology. 2013; 229: 199-208
        • Phelps E.A.
        • Delgado M.R.
        • Nearing K.I.
        • LeDoux J.E.
        Extinction learning in humans: Role of the amygdala and vmPFC.
        Neuron. 2004; 43: 897-905
        • LaBar K.S.
        • Gatenby J.C.
        • Gore J.C.
        • LeDoux J.E.
        • Phelps E.A.
        Human amygdala activation during conditioned fear acquisition and extinction: A mixed-trial fMRI study.
        Neuron. 1998; 20: 937-945
        • Merz C.J.
        • Hermann A.
        • Stark R.
        • Wolf O.T.
        Cortisol modifies extinction learning of recently acquired fear in men.
        Soc Cogn Affect Neurosci. 2014; 9: 1426-1434
        • Hurlemann R.
        • Patin A.
        • Onur O.A.
        • Cohen M.X.
        • Baumgartner T.
        • Metzler S.
        • et al.
        Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans.
        J Neurosci. 2010; 30: 4999-5007
        • Sheehan D.V.
        • Lecrubier Y.
        • Sheehan K.H.
        • Amorim P.
        • Janavs J.
        • Weiller E.
        • et al.
        The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.
        J Clin Psychiatry. 1998; 59: 22-33
        • Guastella A.J.
        • Hickie I.B.
        • McGuinness M.M.
        • Otis M.
        • Woods E.A.
        • Disinger H.M.
        • et al.
        Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research.
        Psychoneuroendocrinology. 2013; 38: 612-625
        • Beck A.T.
        • Steer R.A.
        Internal consistencies of the original and revised Beck Depression Inventory.
        J Clin Psychol. 1984; 40: 1365-1367
        • Peterson R.A.
        • Heilbronner R.L.
        The anxiety sensitivity index: Construct validity and factor analytic structure.
        J Anxiety Disord. 1987; 1: 117-121
        • Becker B.
        • Androsch L.
        • Jahn R.T.
        • Alich T.
        • Striepens N.
        • Markett S.
        • et al.
        Inferior frontal gyrus preserves working memory and emotional learning under conditions of impaired noradrenergic signaling.
        Front Behav Neurosci. 2013; 7: 197
        • Lundqvist D.
        • Flykt A.
        • Öhman A.
        The Karolinska Directed Emotional Faces-KDEF.
        Department of Clinical Neuroscience, Psychology Section, Karolinska Institutet, Stockholm, Sweden, 1998
        • Scheele D.
        • Striepens N.
        • Güntürkün O.
        • Deutschlander S.
        • Maier W.
        • Kendrick K.M.
        • et al.
        Oxytocin modulates social distance between males and females.
        J Neurosci. 2012; 32: 16074-16079
        • Spielberger C.
        • Gorsuch R.
        • Lushene R.
        Manual for the State-Trait Inventory.
        Consulting Psychologists, Palo Alto, CA1970
        • Watson D.
        • Clark L.A.
        • Tellegen A.
        Development and validation of brief measures of positive and negative affect: the PANAS scales.
        J Pers Soc Psychol. 1988; 54: 1063
        • Büchel C.
        • Dolan R.J.
        Classical fear conditioning in functional neuroimaging.
        Curr Opin Neurobiol. 2000; 10: 219-223
        • Evans A.C.
        • Marrett S.
        • Neelin P.
        • Collins L.
        • Worsley K.
        • Dai W.
        • et al.
        Anatomical mapping of functional activation in stereotactic coordinate space.
        Neuroimage. 1992; 1: 43-53
        • Holmes C.J.
        • Hoge R.
        • Collins L.
        • Woods R.
        • Toga A.W.
        • Evans A.C.
        Enhancement of MR images using registration for signal averaging.
        J Comput Assist Tomogr. 1998; 22: 324-333
        • Friston K.J.
        • Holmes A.P.
        • Worsley K.J.
        • Poline J.P.
        • Frith C.D.
        • Frackowiak R.S.J.
        Statistical parametric maps in functional imaging: A general linear approach.
        Hum Brain Mapp. 1994; 2: 189-210
        • Brett M.
        • Anton J.-L.
        • Valabregue R.
        • Poline J.-B.
        Region of interest analysis using the MarsBar toolbox for SPM 99.
        Neuroimage. 2002; 16: S497
        • Lancaster J.L.
        • Woldorff M.G.
        • Parsons L.M.
        • Liotti M.
        • Freitas C.S.
        • Rainey L.
        • et al.
        Automated Talairach atlas labels for functional brain mapping.
        Hum Brain Mapp. 2000; 10: 120-131
        • Maldjian J.A.
        • Laurienti P.J.
        • Kraft R.A.
        • Burdette J.H.
        An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets.
        Neuroimage. 2003; 19: 1233-1239
        • McLaren D.G.
        • Ries M.L.
        • Xu G.
        • Johnson S.C.
        A generalized form of context-dependent psychophysiological interactions (gPPI): A comparison to standard approaches.
        Neuroimage. 2012; 61: 1277-1286
        • Bzdok D.
        • Laird A.R.
        • Zilles K.
        • Fox P.T.
        • Eickhoff S.B.
        An investigation of the structural, connectional, and functional subspecialization in the human amygdala.
        Hum Brain Mapp. 2013; 34: 3247-3266
        • Eckstein M.
        • Scheele D.
        • Weber K.
        • Stoffel-Wagner B.
        • Maier W.
        • Hurlemann R.
        Oxytocin facilitates the sensation of social stress.
        Hum Brain Mapp. 2014; 35: 4741-4750
        • Lahoud N.
        • Maroun M.
        Oxytocinergic manipulations in corticolimbic circuit differentially affect fear acquisition and extinction.
        Psychoneuroendocrinology. 2013; 38: 2184-2195
        • Kovács G.L.
        • Bohus B.
        • Versteeg D.H.
        • De Kloet E.R.
        • De Wied D.
        Effect of oxytocin and vasopressin on memory consolidation: Sites of action and catecholaminergic correlates after local microinjection into limbic-midbrain structures.
        Brain Res. 1979; 175: 303-314
        • 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.
        Psychopharmacology. 223. 2012: 149-158
        • Viviani D.
        • Stoop R.
        Opposite effects of oxytocin and vasopressin on the emotional expression of the fear response.
        Prog Brain Res. 2008; 170: 207-218
        • Zoicas I.
        • Slattery D.A.
        • Neumann I.D.
        Brain oxytocin in social fear conditioning and its extinction: involvement of the lateral septum.
        Neuropsychopharmacology. 2014; 39 (d): 3027-3035
        • Ninan I.
        Oxytocin suppresses basal glutamatergic transmission but facilitates activity-dependent synaptic potentiation in the medial prefrontal cortex.
        J Neurochem. 2011; 119: 324-331
        • Molchan S.E.
        • Sunderland T.
        • McIntosh A.
        • Herscovitch P.
        • Schreurs B.G.
        A functional anatomical study of associative learning in humans.
        Proc Natl Acad Sci U S A. 1994; 91: 8122-8126
        • Yágüez L.
        • Coen S.
        • Gregory L.J.
        • Amaro Jr, E.
        • Altman C.
        • Brammer M.J.
        • et al.
        Brain response to visceral aversive conditioning: A functional magnetic resonance imaging study.
        Gastroenterology. 128. 2005: 1819-1829
        • Graham B.M.
        • Milad M.R.
        The study of fear extinction: Implications for anxiety disorders.
        Am J Psychiatry. 2011; 168: 1255-1265
        • Kober H.
        • Mende-Siedlecki P.
        • Kross E.F.
        • Weber J.
        • Mischel W.
        • Hart C.L.
        • et al.
        Prefrontal-striatal pathway underlies cognitive regulation of craving.
        Proc Natl Acad Sci U S A. 2010; 107: 14811-14816
        • Delgado M.R.
        • Nearing K.I.
        • Ledoux J.E.
        • Phelps E.A.
        Neural circuitry underlying the regulation of conditioned fear and its relation to extinction.
        Neuron. 2008; 59: 829-838
        • Vogt B.A.
        Pain and emotion interactions in subregions of the cingulate gyrus.
        Nat Rev Neurosci. 2005; 6: 533-544
        • Northoff G.
        • Northoff D.
        • Hayes
        Is our self nothing but reward?.
        Biol Psychiatry. 2011; 69: 1019-1025
        • Watanabe T.
        • Abe O.
        • Kuwabara H.
        • et al.
        Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity: A randomized trial.
        JAMA Psychiatry. 2014; 71: 166-175
        • 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: Medial frontal hyperactivity to sad faces in generalized social anxiety disorder and modulation by oxytocin.
        Neuropsychopharmacology. 2010; 35: 2403-2413
        • Sangha S.
        • Chadick J.Z.
        • Janak P.H.
        Safety encoding in the basal amygdala.
        J Neurosci. 2013; 33: 3744-3751
        • Likhtik E.
        • Stujenske J.M.
        • Topiwala M.A.
        • Harris A.Z.
        • Gordon J.A.
        Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety.
        Nat Neurosci. 2014; 17: 106-113
        • Gamer M.
        • Zurowski B.
        • Büchel C.
        Different amygdala subregions mediate valence-related and attentional effects of oxytocin in humans.
        Proc Natl Acad Sci U S A. 2010; 107: 9400-9405
        • Sevelinges Y.
        • Gervais R.
        • Messaoudi B.
        • Granjon L.
        • Mouly A.-M.
        Olfactory fear conditioning induces field potential potentiation in rat olfactory cortex and amygdala.
        Learn Mem. 2004; 11: 761-769
        • Hurlemann R.
        • Rehme A.K.
        • Diessel M.
        • Kukolja J.
        • Maier W.
        • Walter H.
        • et al.
        Segregating intra-amygdalar responses to dynamic facial emotion with cytoarchitectonic maximum probability maps.
        J Neurosci Methods. 2008; 172: 13-20
        • Etkin A.
        • Wager T.D.
        Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.
        Am J Psychiatry. 2007; 164: 1476-1488
        • Labuschagne I.
        • Phan K.L.
        • Wood A.
        • Angstadt M.
        • Chua P.
        • Heinrichs M.
        • et al.
        Medial frontal hyperactivity to sad faces in generalized social anxiety disorder and modulation by oxytocin.
        Int J Neuropsychopharmacol. 2012; 15: 883-896
        • Macdonald K.
        • Macdonald T.M.
        • Brune M.
        • Lamb K.
        • Wilson M.P.
        • Golshan S.
        • et al.
        Oxytocin and psychotherapy: A pilot study of its physiological, behavioral and subjective effects in males with depression.
        Psychoneuroendocrinology. 2013; 27: 00211-00214
        • Meinlschmidt G.
        • Heim C.
        Sensitivity to intranasal oxytocin in adult men with early parental separation.
        Biol Psychiatry. 2007; 61: 1109-1111
        • Scheele D.
        • Kendrick K.M.
        • Khouri C.
        • Kretzer E.
        • Schlapfer T.E.
        • Stoffel-Wagner B.
        • et al.
        An oxytocin-induced facilitation of neural and emotional responses to social touch correlates inversely with autism traits.
        Neuropsychopharmacology. 2014; 39: 2078-2085
        • De Houwer J.
        • Thomas S.
        • Baeyens F.
        Association learning of likes and dislikes: A review of 25 years of research on human evaluative conditioning.
        Psychol Bull. 2001; 127: 853
        • Preckel K.
        • Scheele D.
        • Kendrick K.M.F.
        • Maier W.
        • Hurlemann R.
        Oxytocin facilitates social approach behavior in women.
        Front Behav Neurosci. 2014; 8: 191
        • Scheele D.
        • Striepens N.
        • Kendrick K.M.
        • Schwering C.
        • Noelle J.
        • Wille A.
        • et al.
        Opposing effects of oxytocin on moral judgment in males and females.
        Hum Brain Mapp. 2014; 35: 6067-6076