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An Abrupt Transformation of Phobic Behavior After a Post-Retrieval Amnesic Agent

  • Marieke Soeter
    Affiliations
    Department of Clinical Psychology, Amsterdam, The Netherlands.

    Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, The Netherlands.
    Search for articles by this author
  • Merel Kindt
    Correspondence
    Address correspondence to Merel Kindt, University of Amsterdam, Faculty of Social and Behavioral Sciences, Department of Clinical Psychology, Weesperplein 4, 1018 XA Amsterdam, The Netherlands.
    Affiliations
    Department of Clinical Psychology, Amsterdam, The Netherlands.

    Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, The Netherlands.
    Search for articles by this author

      Abstract

      Background

      Although disrupting the process of memory reconsolidation has a great potential for clinical practice, the fear-amnesic effects are typically demonstrated through Pavlovian conditioning. Given that older and stronger memories are generally more resistant to change, we tested whether disrupting reconsolidation would also diminish fear in individuals who had developed a persistent spider fear outside the laboratory.

      Methods

      Spider-fearful participants received a single dose of 40 mg of the noradrenergic β-blocker propranolol (n = 15), double-blind and placebo-controlled (n = 15), after a short 2-min exposure to a tarantula. To test whether memory reactivation was necessary to observe a fear-reducing effect, one additional group of spider-fearful participants (n = 15) received a single dose of 40 mg propranolol without memory reactivation.

      Results

      Disrupting reconsolidation of fear memory transformed avoidance behavior into approach behavior in a virtual binary fashion—an effect that persisted at least 1 year after treatment. Interestingly the β-adrenergic drug did initially not affect the self-declared fear of spiders but instead these reports followed the instant behavioral transformation several months later.

      Conclusions

      Our findings are in sharp contrast with the currently pharmacological and cognitive behavioral treatments for anxiety and related disorders. The β-adrenergic blocker was only effective when the drug was administered upon memory reactivation, and a modification in cognitive representations was not necessary to observe a change in fear behavior. A new wave of treatments that pharmacologically target the synaptic plasticity underlying learning and memory seems to be within reach.

      Keywords

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      References

        • Nader K.
        • Schafe G.E.
        • LeDoux J.E.
        Fear memories require protein synthesis in the amgydala for reconsolidation after retrieval.
        Nature. 2000; 406: 722-726
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        American Psychiatric Association, Washington DC2000
        • Mineka S.
        • Zinbarg R.
        A contemporary learning theory perspective on anxiety disorders: It’s not what you thought it was.
        Am Psychol. 2006; 61: 10-26
        • Rachman S.
        The conditioning theory of fear acquisition: a critical examination.
        Behav Res Ther. 1977; 15: 375-387
        • Kindt M.
        A behavioral neuroscience perspective on the aetiology and treatment of anxiety disorders.
        Behav Res Ther. 2014; 62: 24-36
        • Baeyens F.
        • De Houwer J.
        Evaluative conditioning is a qualitatively distinct form of classical conditioning: A reply to Davey (1994).
        Behav Res Ther. 1995; 33: 825-831
        • Herman D.
        • Vansteenwegen D.
        • Crombez G.
        • Baeyens F.
        • Eelen P.
        Expectancy-learning and evaluative learning in human classical conditioning: Affective priming as an indirect and unobtrusive measure of conditioned stimulus valence.
        Behav Res Ther. 2002; 40: 217-234
        • Brunet A.
        • Orr S.P.
        • Tremblay J.
        • Robertson K.
        • Nader K.
        • Pitman R.K.
        Effect of post-retrieval propranolol on psychophysiological responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder.
        J Psych Res. 2008; 42: 503-506
        • Nader K.
        • Hardt O.
        A single standard for memory: The case for reconsolidation.
        Nat Rev Neurosci. 2009; 10: 2240234
        • Kindt M.
        • Soeter M.
        • Vervliet B.
        Beyond extinction: Erasing human fear responses and preventing the return of fear.
        Nat Neurosci. 2009; 12: 256-258
        • Soeter M.
        • Kindt M.
        Disrupting reconsolidation: pharmacological and behavioral manipulations.
        Learn Mem. 2011; 18: 357-366
        • Soeter M.
        • Kindt M.
        Stimulation of the noradrenergic system during memory formation impairs extinction learning but not the disruption of reconsolidation.
        Neuropsychopharmacology. 2012; 37: 1204-1215
        • Sevenster D.
        • Beckers T.
        • Kindt M.
        Prediction error governs pharmacologically induced amnesia for learned fear.
        Science. 2013; 339: 830-833
        • Josselyn S.A.
        • Shi C.
        • Carlezon Jr, W.A.
        • Neve R.L.
        • Nestler E.J.
        • Davis M.
        Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala.
        J Neurosci. 2001; 21: 2404-2412
        • Johansen J.P.
        • Cain C.K.
        • Ostroff L.E.
        • LeDoux J.E.
        Molecular mechanisms of fear learning and memory.
        Cell. 2011; 147: 509-524
        • Foa E.B.
        • Kozak M.J.
        Exposure to corrective information.
        Psychol Bull. 1986; 99: 20-35
        • Beckers T.
        • Krypotos A.-M.
        • Boddez Y.
        • Effting M.
        • Kindt M.
        What’s wrong with fear conditioning?.
        Biol Psychol. 2013; 92: 90-96
        • LeDoux J.E.
        Coming to terms with fear.
        PNAS. 2014; 111: 2871-2878
        • Suzuki A.
        • Josselyn S.A.
        • Frankland P.W.
        • Masushige S.
        • Silva A.J.
        • Kida S.
        Memory reconsolidation and extinction have distinct temporal and biochemical signatures.
        J Neurosci. 2004; 24: 4787-4795
        • Wood N.E.
        • Rosasco M.L.
        • Suris A.M.
        • Spring J.D.
        • Marin M.-F.
        • Lasko N.B.
        • et al.
        Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: Three negative psychophysiological studies.
        Psych Res. 2015; 225: 31-39
        • Laxmi T.R.
        • Stork O.
        • Pape H.C.
        Generalization of conditioned fear and its behavioural expression in mice.
        Behav Brain Res. 2003; 145: 89-98
        • Han J.H.
        • Yiu A.P.
        • Cole C.J.
        • Hsiang H.L.
        • Neve R.L.
        • Josselyn S.A.
        Increasing CREB in the auditory thalamus enhances memory and generalization of auditory conditioned fear.
        Learn Mem. 2008; 15: 443-453
        • Sun H.S.
        • Green T.A.
        • Theobald D.E.H.
        • Laali S.
        • Shrikhande G.
        • Birbaum S.
        • et al.
        The pharmacological stressor yohimbine increases impulsivity through activation of CREB in the orbitofrontal cortex.
        Biol Psych. 2010; 67: 649-656
        • Soeter M.
        • Kindt M.
        Erasing fear for an imagined threat event.
        Psychoneuroendocrinology. 2012; 11: 1769-1779
        • Ehlers A.
        • Clark D.M.
        A cognitive model of posttraumatic stress disorder.
        Behav Res Ther. 2000; 38: 319-345
        • Barlow D.H.
        Anxiety and Its Disorders: The Nature and Treatment of Anxiety and Panic.
        Guilford Press, New York2002
        • Sevenster D.
        • Beckers T.
        • Kindt M.
        Retrieval per se is not sufficient to trigger reconsolidation of human fear memory.
        Neurobiol Learn Mem. 2012; 97: 338-345
        • Lee J.L.C.
        Reconsolidation: maintaining memory relevance.
        Trends Neurosci. 2009; 32: 413-420
        • Merlo E.
        • Milton A.L.
        • Goozée Z.Y.
        • Theobald D.E.
        • Everitt B.J.
        Reconsolidation and extinction are dissociable and mutually exclusive processes: Behavioral and molecular evidence.
        J Neurosci. 2014; 34: 2422-2431
        • Sevenster D.
        • Beckers T.
        • Kindt M.
        Prediction error demarcates the transition from retrieval, to reconsolidation, to new learning.
        Learn Mem. 2014; 21: 580-584
        • Klorman R.
        • Weerts T.C.
        • Hastings J.E.
        • Melamed G.B.G.
        • Lang P.
        Psychometric description of some specific fear questionnaires.
        Behav Ther. 1974; 5: 401-409
        • Wolpe J.
        Practice of Behavior Therapy. Pergamon Press, New York1973
        • Rodriguez B.
        • Craske M.G.
        • Mineka S.
        • Hladek D.
        Context-specificity of relapse: effects of therapist and environmental context on return of fear.
        Behav Res Ther. 1999; 37: 845-862
        • Spielberger C.
        • Gorsuch R.
        • Lusthene R.
        Manual for the State-Trait Anxiety Inventory.
        Consulting PP, Palo Alto1970
        • Peterson R.
        • Reiss S.
        Anxiety Sensitivity Index Manual.
        International, Worthington, DC1992
        • Beck A.
        Depression: Causes and Treatment.
        UP Press, Philadelphia1967
        • First M.
        Structured Clinical Interview for DSM-IV Axis-I Disorders.
        American Psychiatric Press, Washington, DC1997
        • Gilman A.
        • Goodman L.
        Goodman and Gilmans the Pharmacological Basis of Therapeutics.
        McGraw-Hill, New York1996
        • Muris P.
        • Merckelbach J.
        A comparison of two spider fear questionnaires.
        J Behav Ther Exp Psych. 1996; 27: 241-244
        • Roozendaal B.
        • Quirarte G.L.
        • McGaugh J.L.
        Glucocorticoids interact with the basolateral amgydala β-adrenoceptor-cAMP-PKA system in influencing memory consolidation.
        Eur J Neurosci. 2002; 15: 553-560
        • McGaugh J.L.
        Amygdala modulates the consolidation of memories of emotionally arousing experiences.
        Ann Rev Neurosci. 2005; 27: 1-28
        • LaBar K.S.
        • Cabeza R.
        Cognitive neuroscience of emotional memory.
        Nat Rev Neurosci. 2006; 7: 54-64
        • Hermans D.
        • Craske M.G.
        • Mineka S.
        • Lovibond P.F.
        Extinction in human fear conditioning.
        Biol Psych. 2006; 60: 361-368
        • Hermans D.
        • Dirikx T.
        • Vansteenwegen D.
        • Baeyens F.
        • Bergh van den O.
        • Eelen O.
        Reinstatement of fear responses in human aversive conditioning.
        Behav Res Ther. 2005; 43: 533-551
        • Dirikx T.
        • Hermans D.
        • Vansteenwegen D.
        • Baeyens F.
        • Eelen P.
        Reinstatement of extinguished conditioned responses and negative stimulus valence as a pathway to return of fear in humans.
        Learn Mem. 2004; 11: 549-555
        • Dirikx T.
        • Hermans D.
        • Vansteenwegen D.
        • Baeyens F.
        • Eelen P.
        Reinstatement of conditioned responses in human differential fear conditioning.
        J Behav Ther Exp Psych. 2007; 38: 237-251
        • Soeter M.
        • Kindt M.
        Dissociating response systems: erasing fear from memory.
        Neurobiol Learn Mem. 2010; 30: 4990-4998
        • Bouton M.
        Context and behavioral processes in extinction.
        Learn Mem. 2004; 11: 485-494
        • Clark D.A.
        Perceived limitations of standard cognitive therapy: A reconsideration of efforts to revise Becks theory and therapy.
        J Cogn Psychother. 1995; 9: 153-172
        • Bouton M.E.
        Context, ambiguity, and unlearning: sources of relapse after behavioral extinction.
        Biol Psych. 2002; 52: 976-986
        • Bouton M.E.
        Context, time, and memory retrieval in the interference paradigms of Pavlovian learning.
        Psychol Bull. 1993; 114: 80-99
        • LeDoux J.E.
        Emotion: clues from the brain.
        Ann Rev Psychol. 1995; 46: 209-235
        • Craske M.G.
        Anxiety Disorders: Psychological Approaches to Theory and Treatment.
        Westview Press, Boulder1999
        • Durham R.C.
        • Higgins C.
        • Chambers J.A.
        • Swan J.S.
        • Dow M.G.T.
        Long-term outcome of eight clinical trials of CBT for anxiety disorders: Symptom profile of sustained recovery and treatment-resistant groups.
        J Affect Dis. 2012; 136: 875-881
        • Craske M.G.
        • Treanor M.
        • Conway C.C.
        • Zbozinek T.
        • Vervliet B.
        Maximizing exposure therapy: an inhibitory learning approach.
        Behav Res Ther. 2014; 58: 10-23
        • Graham B.M.
        • Callaghan B.L.
        • Richardson R.
        Bridging the gap: Lessons we have learnt from the merging of psychology and psychiatry for the optimization of treatments for emotional disorders.
        Behav Res Ther. 2014; 62: 3-16
        • Milad M.R.
        • Rosenbaum B.L.
        • Simon N.M.
        Neuroscience of fear extinction: Implications for assessment and treatment of fear-based and anxiety related disorders.
        Behav Res Ther. 2014; 62: 17-23
        • Pedreira M.E.
        • Perez-Cuesta L.M.
        • Maldonado H.
        Mismatch between what is expected and what actually occurs triggers memory reconsolidation or extinction.
        Learn Mem. 2004; 11: 579-585

      Linked Article

      • Harnessing Reconsolidation to Treat Mental Disorders
        Biological PsychiatryVol. 78Issue 12
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          In the 1990s, LeDoux, a prominent behavioral neuroscientist, asserted the proposition that “emotional memory may be forever” (1). Not addressed was the question how anything can last forever, especially something preserved in a gelatinous blob of cholesterol, phospholipids, glycerophosphatides, sphingomyelin, and other substances. “This too shall pass.”
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