Advertisement

Pharmacotherapy in the Aftermath of Trauma; Opportunities in the ‘Golden Hours’

  • Eric Vermetten
  • Joseph Zhohar
  • Harm J. Krugers
Anxiety Disorders (DJ Stein, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Anxiety Disorders

Abstract

Several lines of research have demonstrated that memories for fearful events become transiently labile upon re-exposure. Activation of molecular mechanisms is required in order to maintain retrieved information. This process is called reconsolidation. Targeting reconsolidation — as in exposure-based psychotherapy — offers therefore a potentially interesting tool to manipulate fear memories, and subsequently to treat disorders such as post-traumatic stress disorder (PTSD). In this paper we discuss the evidence for reconsolidation in rodents and humans and highlight recent studies in which clinical research on normal and abnormal fear extinction reduction of the expression of fear was obtained by targeting the process of reconsolidation. We conclude that reconsolidation presents an interesting opportunity to modify or alter fear and fear-related memories. More clinical research on normal and abnormal fear extinction is required.

Keywords

Post-traumatic stress disorder Prevention Reconsolidation Synapses Cortisol Propranolol Animal model 

Notes

Compliance with Ethics Guidelines

Conflict of Interest

Eric Vermetten, Joseph Zhohar, and Harm J. Krugers declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Abrari K, Rashidy-Pour A, Semnanian S, Fathollahi Y. Administration of corticosterone after memory reactivation disrupts subsequent retrieval of a contextual conditioned fear memory: dependence upon training intensity. Neurobiol Learn Mem. 2008;89:178–84.PubMedGoogle Scholar
  2. 2.
    Alberini CM. Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes? Trends Neurosci. 2005;28:51–6.PubMedGoogle Scholar
  3. 3.
    Boehnlein JK, Kinzie JD. Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin. J Psychiatr Pract. 2007;13:72–8.PubMedGoogle Scholar
  4. 4.
    Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J Psychiatr Res. 2008;42:503–6.PubMedGoogle Scholar
  5. 5.
    Brunet A, Poundja J, Tremblay J, Bui E, Thomas E, Orr SP, et al. Trauma reactivation under the influence of propranolol decreases posttraumatic stress symptoms and disorder: 3 open-label trials. J Clin Psychopharmacol. 2011;31:547–50.PubMedGoogle Scholar
  6. 6.
    Cahill L, Alkire MT. Epinephrine enhancement of human memory consolidation: Interaction with arousal at encoding. Neurobiol Learn Mem. 2003;79:194–8.PubMedGoogle Scholar
  7. 7.
    Cahill L, Prins B, Weber M, McGaugh JL. Beta-adrenergic activation and memory for emotional events. Nature. 1994;371:702–4.PubMedGoogle Scholar
  8. 8.
    Cai WH, Blundell J, Han J, Greene RW, Powell CM. Postreactivation glucocorticoids impair recall of established fear memory. J Neurosci. 2006;26:9560–6.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Campolongo P, Roozendaal B, Trezza V, Hauer D, Schelling G, McGaugh JL, et al. Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory. Proc Natl Acad Sci U S A. 2009;106:4888–93.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Champagne DL, Bagot RC, van Hasselt F, Ramakers G, Meaney MJ, de Kloet ER, et al. Maternal care and hippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. J Neurosci. 2008;28:6037–45.PubMedGoogle Scholar
  11. 11.
    Charney DS, Woods SW, Goodman WK, Heninger GR. Neurobiological mechanisms of panic-anxiety: biochemical and behavioural correlates of yohimbine-induced panic attacks. Am J Psychiatry. 1987;44:1030–6.Google Scholar
  12. 12.
    Clem RL, Huganir RL. Calcium-permeable AMPA receptor dynamics mediate fear memory erasure. Science. 2010;330:1108–12.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Corodimas KP, LeDoux JE, Gold PW, Schulkin J. Corticosterone potentiation of conditioned fear in rats. Ann N Y Acad Sci. 1994;746:392–3.PubMedGoogle Scholar
  14. 14.••
    Das RK, Freeman TP, Kamboj SK. The effects of N-methyl D-aspartate and B-adrenergic receptor antagonists on the reconsolidation of reward memory: a meta-analysis. Neurosci Biobehav Rev. 2013;37:240–55. This paper reviews two of the most promising classes of drug that interfere with reconsolidation and have translational potential for human use are N-methyl-D-aspartate receptor (NMDAR) and B-Adrenergic receptor (B-AR) antagonists. An analysis of 52 independent effect sizes (NMDAR=30, B-AR=22) found robust effects of both classes of drug on memory reconsolidation, but a far greater overall effect of NMDAR antagonism than B-AR antagonism. PubMedGoogle Scholar
  15. 15.
    Davis M, Ressler K, Rothbaum BO, Richardson R. Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry. 2006;60:369–75.PubMedGoogle Scholar
  16. 16.
    Debiec J, LeDoux JE, Nader K. Cellular and systems reconsolidation in the hippocampus. Neuron. 2002;36:527–38.PubMedGoogle Scholar
  17. 17.
    Debiec J, LeDoux JE. Noradrenergic signaling in the amygdala contributes to the reconsolidation of fear memory: treatment implications for PTSD. Ann NY Acad Sci. 2006;1071:521–4.PubMedGoogle Scholar
  18. 18.
    de Kloet ER, Oitzl MS, Joels M. Stress and Cognition: are corticosteroids good or bad guys? Trends Neurosci. 1999;22:422–6.PubMedGoogle Scholar
  19. 19.
    de Kloet ER, Joëls M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6:463–75.PubMedGoogle Scholar
  20. 20.
    de Quervain DJ, Roozendaal B, McGaugh JL. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature. 1998;394:787–90.PubMedGoogle Scholar
  21. 21.
    de Quervain DJ, Aerni A, Schelling G, Roozendaal B. Glucocorticoids and the regulation of memory in health and disease. Front Neuroendocrinol. 2009;30:358–70.PubMedGoogle Scholar
  22. 22.
    Di S, Malcher-Lopes R, Halmos KC, Tasker JG. Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci. 2003;23:4850–7.PubMedGoogle Scholar
  23. 23.
    Diergaarde L, Schoffelmeer AN, De Vries TJ. Pharmacological manipulation of memory reconsolidation: towards a novel treatment of pathogenic memories. Eur J Pharmacol. 2008;585:453–7.PubMedGoogle Scholar
  24. 24.
    Difede J, Cukor J, Wyka K, Olden M, Hoffman H, Lee FS, et al. D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial. Neuropsychopharmacology. 2013. doi: 10.1038/npp.2013.317.PubMedGoogle Scholar
  25. 25.
    Dudai Y. The neurobiology of consolidations, or, how stable is the engram? Annu Rev Psychol. 2004;55:51–86.PubMedGoogle Scholar
  26. 26.
    Dudai. Reconsolidation: the advantage of being refocused. Curr Opin Neurobiol. 2006;16:174–8.PubMedGoogle Scholar
  27. 27.
    Ehlers A, Hackmann A, Michael T. Intrusive re-experiencing in post-traumatic stress disorder: phenomenology, theory, and therapy. Memory. 2004;12:403–15.PubMedGoogle Scholar
  28. 28.•
    Gamache K, Pitman RK, Nader K. Preclinical evaluation of reconsolidation blockade by clonidine as a potential novel treatment for posttraumatic stress disorder. Neuropsychopharmacology. 2012;37:2789–96. Another example of golden hour opportunity: this study provides important preclinical parameters for future therapeutic strategies involving clonidine α2-adrenoreceptor agonist to block reconsolidation as a novel treatment for PTSD symptoms.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Gibbs ME, Summers RJ. Role of adrenoceptor subtypes in memory consolidation. Prog Neurobiol. 2002;67:345–91.PubMedGoogle Scholar
  30. 30.•
    Giese KP, Mizuno K. The roles of protein kinases in learning and memory. Learn Mem. 2013;20:540–52. A review paper on the role of the learning and memory-related kinases in short-term memory formation, memory consolidation, memory storage, retrieval, reconsolidation, and extinction. PubMedGoogle Scholar
  31. 31.
    Groc L, Choquet D, Chaouloff F. The stress hormone corticosterone conditions AMPAR surface trafficking and synaptic potentiation. 2008;11:868–70.Google Scholar
  32. 32.••
    Hauger RL, Olivares-Reyes JA, Dautzenberg FM, Lohr JB, Braun S, Oakley RH. Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy. Neuropharmacology. 2012;62:705–14. This highly interesting paper reviews key genetic diatheses and molecular targets especially signaling pathways that mediate responses to trauma and severe stress and their potential contribution to the etiology of PTSD. The perspective is from sensitization of glucocorticoid receptor (GR) signaling and dysregulation of GR modulators FKBP5, STAT5B, Bcl-2, and Bax; all implicated in PTSD pathophysiology. PubMedCentralPubMedGoogle Scholar
  33. 33.
    Herringa RJ, Birn RM, Ruttle PL, Burghy CA, Stodola DE, Davidson RJ, et al. Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence. Proc Natl Acad Sci U S A. 2013;110:19119–24.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Het S, Ramlow G, Wolf OT. A meta-analytic review of the effects of acute cortisol administration on human memory. Psychoneuroendocrinology. 2005;30:771–84.PubMedGoogle Scholar
  35. 35.
    Hoge EA, Worthington JJ, Nagurney JT, Chang Y, Kay EB, Feterowski CM, et al. Effect of acute posttrauma propranolol on PTSD outcome and physiological responses during script-driven imagery. CNS Neurosci Ther. 2012;18:21–7.PubMedGoogle Scholar
  36. 36.•
    Hong I, Kim J, Kim J, Lee S, Ko HG, Nader K, et al. AMPA receptor exchange underlies transient memory destabilization on retrieval. Proc Natl Acad Sci U S A. 2013;110:8218–23. This paper shows that at lateral amygdala synapses, fear memory consolidation correlates with increased surface expression of calcium-impermeable AMPA receptors (CI-AMPARs), known to be more stable at the synapse, whereas memory retrieval induces an abrupt exchange of CI-AMPARs to calcium-permeable AMPARs (CP-AMPARs), known to be less stable at the synapse. These are unexpected physiological roles of CI-AMPARs and CP-AMPARs in transforming a consolidated memory into an unstable memory and subsequently guiding reconsolidation. PubMedCentralPubMedGoogle Scholar
  37. 37.
    Hu H, Real E, Takamiya K, Kang M, Ledoux JE, Huganir RL, et al. Emotion enhances learning via norepinephrine regulation of AMPA-Receptor trafficking. Cell. 2007;131:160–73.PubMedGoogle Scholar
  38. 38.
    Hui GK, Figueroa IR, Poytress BS, Roozendaal B, McGaugh JL, Weinberger NM. Memory enhancement of classical fear conditioning by post-training injections of corticosterone in rats. Neurobiol Learn Mem. 2004;81:67–74.PubMedGoogle Scholar
  39. 39.
    Ipser JC, Stein DJ. Evidence-based pharmacotherapy of post-traumatic stress disorder (PTSD). Int J Neuropsychopharmacol / Off Sci J Coll Int Neuropsychopharmacol. 2012;15:825–40.Google Scholar
  40. 40.
    Jeffreys M, Capehart B, Friedman MJ. Pharmacotherapy for posttraumatic stress disorder: review with clinical applications. J Rehabil Res Dev. 2012;49:703–15.PubMedGoogle Scholar
  41. 41.
    Ji JZ, Wang XM, Li BM. Deficit in long-term contextual fear memory induced by blockade of beta-adrenoceptors in hippocampal CA1 region. Eur J Neurosci. 2003;17:1947–52.PubMedGoogle Scholar
  42. 42.
    Joëls M, Pu Z, Wiegert O, Oitzl MS, Krugers HJ. Learning under stress: how does it work? Trends Cogn Sci. 2006;10:152–8.PubMedGoogle Scholar
  43. 43.
    Joëls M, Baram TZ. The neuro-symphony of stress. Nat Rev Neurosci. 2009;10:459–66.PubMedCentralPubMedGoogle Scholar
  44. 44.•
    Joëls M, Fernandez G, Roozendaal B. Stress and emotional memory: a matter of timing. Trends Cogn Sci. 2011;15:280–8. This paper shows the importance of a dynamic interaction in the adaptive and potentially protective capacity of corticosteroids regarding traumatic memories. PubMedGoogle Scholar
  45. 45.
    Kandel ER. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain. 2012;5:14.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Karst H, Berger S, Turiault M, Tronche F, Schütz G, Joëls M. Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci U S A. 2005;102:19204–7.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Karst H, Berger S, Erdmann G, Schütz G, Joëls M. Metaplasticity of amygdalar responses to the stress hormone corticosterone. Proc Natl Acad Sci U S A. 2010;107:14449–54.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Kessels HW, Malinow R. Synaptic AMPA receptor plasticity and behaviour. Neuron. 2009;61:340–50.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Kindt M, Soeter M, Vervliet B. Beyond extinction: erasing human fear responses and preventing the return of fear. Nat Neurosci. 2009;12:256–8.PubMedGoogle Scholar
  50. 50.
    Kindt M, Soeter M. Reconsolidation in a human fear conditioning study: a test of extinction as updating mechanism. Biol Psychol. 2013;92:43–50.PubMedGoogle Scholar
  51. 51.
    Kim P, Evans GW, Angstadt M, Ho SS, Sripada CS, Swain JE, et al. Effects of childhood poverty and chronic stress on emotion regulatory brain function in adulthood. Proc Natl Acad Sci U S A. 2013;110:18442–7.PubMedCentralPubMedGoogle Scholar
  52. 52.
    de Kleine RA, Hendriks GJ, Smits JA, Broekman TG, van Minnen A. Prescriptive variables for d-cycloserine augmentation of exposure therapy for posttraumatic stress disorder. J Psychiatr Res. 2014;48:40–6.PubMedGoogle Scholar
  53. 53.•
    de Kleine RA, Rothbaum BO, van Minnen A. Pharmacological enhancement of exposure-based treatment in PTSD: a qualitative review. Eur J Psychotraumatol. 2013;4 The paper provides an overview of clinical studies on pharmacological enhancement of exposure-based treatment for PTSD. Google Scholar
  54. 54.
    de Kleine RA, Hendriks GJ, Kusters WJ, Broekman TG, van Minnen A. A randomized placebo-controlled trial of D-cycloserine to enhance exposure therapy for posttraumatic stress disorder. Biol Psychiatry. 2012;71:962–8.PubMedGoogle Scholar
  55. 55.•
    Kroes MC, Tendolkar I, van Wingen GA, van Waarde JA, Strange BA, Fernández G. An electroconvulsive therapy procedure impairs reconsolidation of episodic memories in humans. Nat Neurosci. 2013. doi: 10.1038/nn.3609. This paper reports evidence for reconsolidation of emotional episodic memories in humans. Single application of electroconvulsive therapy following memory reactivation in patients with depression disrupted reactivated, but not non-reactivated, memories for an emotional episode. PubMedGoogle Scholar
  56. 56.
    Krugers HJ, Hoogenraad CC, Groc L. Stress hormones and AMPA receptor trafficking in synaptic plasticity and memory. Nat Rev Neurosci. 2010;11:675–81.PubMedGoogle Scholar
  57. 57.
    Lonergan MH, Olivera-Figueroa LA, Pitman RK, Brunet A. Propranolol’s effects on the consolidation and reconsolidation of long-term emotional memory in healthy participants: a meta-analysis. J Psychiatry Neurosci. 2013;38:222–31.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Makino H, Malinow R. AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron. 2009;64:381–90.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002;25:103–26.PubMedGoogle Scholar
  60. 60.•
    Marin MF, Hupbach A, Maheu FS, Nader K, Lupien SJ. Metyrapone administration reduces the strength of an emotional memory trace in a long-lasting manner. J Clin Endocrinol Metab. 2011;96:1221–7. This paper demonstrated that decreasing GC levels via metyrapone administration is an efficient way to reduce the strength of an emotional memory in a long-lasting manner. Google Scholar
  61. 61.
    McGaugh JL. Memory–a century of consolidation. Science. 2000;287:248–51.PubMedGoogle Scholar
  62. 62.
    Mitsushima D, Ishihara K, Sano A, Kessels HW, Takahashi T. Contextual learning requires synaptic AMPA receptor delivery in the hippocampus. Proc Natl Acad Sci U S A. 2011;108:12503–8.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Monfils MH, Cowansage KK, Klann E, LeDoux JE. Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science. 2009;324:951–5.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Nader K, Schafe GE, Le Doux JE. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature. 2000;406:722–6.PubMedGoogle Scholar
  65. 65.
    Nader K, Schafe GE, LeDoux JE. The labile nature of consolidation theory. Nat Rev Neurosci. 2000;1:216–9.PubMedGoogle Scholar
  66. 66.
    Nader K, Einarsson EO. Memory reconsolidation: an update. Ann NY Acad Sci. 2010;1191:27–41.PubMedGoogle Scholar
  67. 67.
    Neves G, Cooke SF, Bliss TV. Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci. 2008;9:65–75.PubMedGoogle Scholar
  68. 68.
    Oitzl MS, de Kloet ER. Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning. Behav Neurosci. 1992;106:62–71.PubMedGoogle Scholar
  69. 69.
    Oomen CA, Soeters H, Audureau N, Vermunt L, van Hasselt FN, Manders EM, et al. Severe early life stress hampers spatial learning and neurogenesis, but improves hippocampal synaptic plasticity and emotional learning under high-stress conditions in adulthood. J Neurosci. 2010;30:6635–45.PubMedGoogle Scholar
  70. 70.
    Orchinik M, Murray TF, Moore FL. A corticosteroid receptor in neuronal membranes. Science. 1991;252:1848–51.PubMedGoogle Scholar
  71. 71.
    Peskind ER, Wingerson D, Murray S, Pascualy M, Dobie DJ, Le Corre P, et al. Effects of Alzheimer’s disease and normal aging on cerebrospinal fluid norepinephrine responses to yohimbine and clonidine. Arch Gen Psychiatry. 1995;52:774–82.PubMedGoogle Scholar
  72. 72.
    Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, Lasko NB, et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry. 2002;51:189–92.PubMedGoogle Scholar
  73. 73.•
    Pitman RK, Milad MR, Igoe SA, Vangel MG, Orr SP, Tsareva A, et al. Systemic mifepristone blocks reconsolidation of cue-conditioned fear; propranolol prevents this effect. Behav Neurosci. 2011;125:632–8. Highly interesting paper that evaluated the ability of postreactivation mifepristone (RU38486, a glucocorticoid antagonist), alone and in combination with propranolol (a beta-adrenergic blocker), both given systemically, to reduce cue-conditioned fear in rats. It was shown that postreactivation mifepristone may be a promising treatment for PTSD, but not necessarily in combination with propranolol. PubMedGoogle Scholar
  74. 74.
    Pugh CR, Fleshner M, Rudy JW. Type II glucocorticoid receptor antagonists impair contextual but not auditory-cue fear conditioning in juvenile rats. Neurobiol Learn Mem. 1997;67:75–9.PubMedGoogle Scholar
  75. 75.
    Pugh CR, Tremblay D, Fleshner M, Rudy JW. A selective role for corticosterone in contextual-fear conditioning. Behav Neurosci. 1997;111:503–11.PubMedGoogle Scholar
  76. 76.
    Rao-Ruiz P, Rotaru DC, van der Loo RJ, Mansvelder HD, Stiedl O, Smit AB, et al. Retrieval-specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fear. Nat Neurosci. 2011;14:1302–8.PubMedGoogle Scholar
  77. 77.
    Roozendaal B, Schelling G, McGaugh JL. Corticotropin-releasing factor in the basolateral amygdala enhances memory consolidation via an interaction with the beta-adrenoceptor-cAMP pathway: dependence on glucocorticoid receptor activation. J Neurosci. 2008;28:6642–51.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Roozendaal B, Okuda S, Van der Zee EA, McGaugh JL. Glucocorticoid enhancement of memory requires arousal-induced noradrenergic activation in the basolateral amygdala. Proc Natl Acad Sci U S A. 2006;103:6741–676.PubMedCentralPubMedGoogle Scholar
  79. 79.
    Roozendaal B, McEwen BS, Chattarji S. Stress, memory and the amygdala. Nat Rev Neurosci. 2009;10:423–33.PubMedGoogle Scholar
  80. 80.
    Rumpel S, LeDoux J, Zador A, Malinow R. Postsynaptic receptor trafficking underlying a form of associative learning. Science. 2005;308:83–8.PubMedGoogle Scholar
  81. 81.
    Sandi C, Rose SP. Corticosterone enhances long-term retention in one-day-old chicks trained in a weak passive avoidance learning paradigm. Brain Res. 1994;647:106–12.PubMedGoogle Scholar
  82. 82.
    Schiller D, Monfils MH, Raio CM, Johnson DC, Ledoux JE, Phelps EA. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature. 2010;463:49–53.PubMedCentralPubMedGoogle Scholar
  83. 83.•
    Schneier FR, Neria Y, Pavlicova M, Hembree E, Suh EJ, Amsel L, et al. Combined prolonged exposure therapy and paroxetine for PTSD related to the World Trade Center attack: a randomized controlled trial. Am J Psychiatry. 2012;169:80–8. One of the first studies that combined treatment in PTSD: treatment with paroxetine plus prolonged exposure was more efficacious than prolonged exposure plus placebo for PTSD. It was part of a call to looking into combined treatment of medication and prolonged exposure therapy. PubMedCentralPubMedGoogle Scholar
  84. 84.
    Schwabe L, Schächinger H, de Kloet ER, Oitzl MS. Corticosteroids operate as a switch between memory systems. J Cogn Neurosci. 2010;22:1362–72.PubMedGoogle Scholar
  85. 85.•
    Smits JA, Rosenfield D, Otto MW, Powers MB, Hofmann SG, Telch MJ, et al. D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia. Biol Psychiatry. 2013;73:1054–8. This paper presents important results demonstrating the efficacy of DCS for augmenting exposure-based CBT depends on the success of exposure sessions (as indexed by end fear). PubMedCentralPubMedGoogle Scholar
  86. 86.
    Soeter M, Kindt M. Dissociating response systems: erasing fear from memory. Neurobiol Learn Mem. 2010;94:30–41.PubMedGoogle Scholar
  87. 87.
    Soeter M, Kindt M. Disrupting reconsolidation: pharmacological and behavioral manipulations. Learn Mem. 2011;18:357–66.PubMedGoogle Scholar
  88. 88.
    Soravia LM, Heinrichs M, Aerni A, Maroni C, Schelling G, Ehlert U, et al. Glucocorticoids reduce phobic fear in humans. Proc Natl Acad Sci U S A. 2006;103:5585–90.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Southwick SM, Davis M, Horner B, Cahill L, Morgan CA, Gold PE, et al. Relationship of enhanced norepinephrine activity during memory consolidation to enhanced long-term memory in humans. Am J Psychiatry. 2002;159:1420–2.PubMedGoogle Scholar
  90. 90.
    Stein, D.J., Ipser, J.C., Seedat, S., 2006. Pharmacotherapy for posttraumatic stress disorder (PTSD). The Cochrane database of systematic reviews, CD002795.Google Scholar
  91. 91.•
    Suris A, Smith J, Powell C, North CS. Interfering with the reconsolidation of traumatic memory: sirolimus as a novel agent for treating veterans with posttraumatic stress disorder. Ann Clin Psychiatry Off J Am Acad Clin Psychiatr. 2013;25:33–40. This interesting paper studied pairing of sirolimus with traumatic memory reactivation. In Vietnam-era veterans who had recent combat trauma, PTSD symptom scores fell significantly. Google Scholar
  92. 92.
    Tenorio G, Connor SA, Guévremont D, Abraham WC, Williams J, O’Dell TJ, et al. ‘Silent’ priming of translation-dependent LTP by ß-adrenergic receptors involves phosphorylation and recruitment of AMPA receptors. Learn Mem. 2010;23:627–38.Google Scholar
  93. 93.
    Thomas MJ, Moody TD, Makhinson M, O’Dell TJ. Activity-dependent beta-adrenergic modulation of low frequency stimulation induced LTP in the hippocampal CA1 region. Neuron. 1996;17:475–82.PubMedGoogle Scholar
  94. 94.•
    Timmermans W, Xiong H, Hoogenraad CC, Krugers HJ. Stress and excitatory synapses: from health to disease. Neuroscience. 2013;248:626–36. This paper addresses how stress regulates brain function and what determines the threshold between adaptive and maladaptive responses. PubMedGoogle Scholar
  95. 95.
    Tronson NC, Taylor JR. Molecular mechanisms of memory reconsolidation. Nat Neurosci Rev. 2007;8:262–75.Google Scholar
  96. 96.
    Tsien JZ, Huerta PT, Tonegawa S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell. 1996;87:1327–38.PubMedGoogle Scholar
  97. 97.
    Van Stegeren AH, Everaerd W, Cahill L, McGaugh JL, Gooren LJG. Memory for emotional events: differential effects of centrally versus peripherally acting β-blocking agents. Psychopharmacology. 1998;138:305–10.PubMedGoogle Scholar
  98. 98.
    Van Stegeren AH. The role of the noradrenergic system in emotional memory. Acta Psychol. 2008;127:532–41.Google Scholar
  99. 99.
    Venero C, Borrell J. Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: a microdialysis study in freely moving rats. Eur J Neurosci. 1999;11:2465–73.PubMedGoogle Scholar
  100. 100.•
    Vermetten E, Lanius RA. Biological and clinical framework for posttraumatic stress disorder. Handb Clin Neurol. 2012;106:291–342. This paper provides a comprehensive overview of the biological and clinical studies in PTSD of the time since its inclusion in DMSIII in 1980. PubMedGoogle Scholar
  101. 101.
    Vetere G, Piserchia V, Borreca A, Novembre G, Aceti M, Ammassari-Teule M. Reactivating fear memory under propranolol resets pre-trauma levels of dendritic spines in basolateral amygdala but not dorsal hippocampus neurons. Front Behav Neurosci. 2013;7:211.PubMedCentralPubMedGoogle Scholar
  102. 102.
    Walker DL, Ressler KJ, Lu KT, Davis M. Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci. 2002;22:2343–23.PubMedGoogle Scholar
  103. 103.
    Walker MP, Brakefield T, Hobson JA, Stickgold R. Dissociable stages of human memory consolidation and reconsolidation. Nature. 2003;425:616–20.PubMedGoogle Scholar
  104. 104.
    Weaver IC, Meaney MJ, Szyf M. Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc Natl Acad Sci U S A. 2006;103:3480–5.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Wolf OT. Stress and memory in humans: twelve years of progress? Brain Res. 2009;1293:142–54.PubMedGoogle Scholar
  106. 106.
    Yehuda R. Status of glucocorticoid alterations in post-traumatic stress disorder. Ann NY Acad Sci. 2009;1179:56–69.PubMedGoogle Scholar
  107. 107.
    Zhou M, Bakker EH, Velzing EH, Berger S, Oitzl M, Joëls M, et al. Both mineralocorticoid and glucocorticoid receptors regulate emotional memory in mice. Neurobiol Learn Mem. 2010;94:530–7.PubMedGoogle Scholar
  108. 108.
    Zohar J, Sonnino R, Juven-Wetzler A, Cohen H. Can posttraumatic stress disorder be prevented? CNS Spectr. 2009;14:44–51.PubMedGoogle Scholar
  109. 109.•
    Zohar J, Yahalom H, Kozlovsky N, Cwikel-Hamzany S, Matar MA, Kaplan Z, et al. High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies. Eur Neuropsychopharmacol. 2011;11:796–809. This paper called for a “window of opportunity” in the early aftermath of trauma to help those who are vulnerable to the development of chronic PTSD. Early single high-dose hydrocortisone intervention attenuated the core symptoms of both the acute stress and of subsequent PTSD in patients. High-dose hydrocortisone treatment given in the first few hours after a traumatic experience was associated with significant favorable changes in the trajectory of exposure to trauma, as expressed by the reduced risk of the development of PTSD post-trauma. Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Eric Vermetten
    • 1
    • 2
    • 3
  • Joseph Zhohar
    • 4
  • Harm J. Krugers
    • 5
  1. 1.Department PsychiatryLeiden University Medical Center UtrechtLeidenThe Netherlands
  2. 2.Arq Psychotrauma Research GroupDiemenThe Netherlands
  3. 3.Military Mental Health Research Ministry of DefenceUtrechtThe Netherlands
  4. 4.Department of PsychiatryChaim Sheba Medical CenterTel HashomerIsrael
  5. 5.Swammerdam Institute for Life SciencesUniversity of AmsterdamAmsterdamThe Netherlands

Personalised recommendations