Abstract
Rationale
The post-extinction exposure of rats to a sub-conditioning procedure (SCP; i.e., retraining with a shock intensity that is too weak to induce by itself significant fear conditioning) has been reported to provoke the reemergence of extinguished fear. This phenomenon can be prevented by chronic fluoxetine treatment.
Objectives
We sought to examine another potential inducer of fear reemergence, acute stress, in rats and determine whether fluoxetine prevents this phenomenon.
Methods
Because in previous studies fluoxetine was administered before extinction, we first analyzed its effect on the SCP-associated reemergence of auditory-cued conditioned fear in rats injected after extinction to avoid any interaction between fluoxetine and extinction learning. Next, we used the same protocol but replaced the SCP with acute stress.
Results
We found that the SCP and acute stress, which were carried out 3 weeks after fear extinction, similarly provoked the reemergence of extinguished fear in rats injected with vehicle during the 3-week period. In contrast, the animals treated with fluoxetine during this period behaved similarly to those not exposed to an inducer of fear reemergence.
Conclusions
Our data establish acute stress as an inducer of fear reemergence. The results provide further support for the hypothesis that fluoxetine interfered with mechanisms that reactivated extinguished fear, even when administered after fear extinction.
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References
Akirav I, Maroun M (2007) The role of the medial prefrontal cortex–amygdala circuit in stress effects on the extinction of fear. Neural Plast 2007:30873
Arnsten AF (2009) Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 10:410–422
Baran SE, Armstrong CE, Niren DC, Hanna JJ, Conrad CD (2009) Chronic stress and sex differences on the recall of fear conditioning and extinction. Neurobiol Learn Mem 91:323–332
Blanchard RJ, Blanchard DC (1968) Limbic lesions and reflexive fighting. J Comp Physiol Psychol 66:603–605
Bouton ME, Bolles RC (1979) Role of conditioned contextual stimuli in reinstatement of extinguished fear. J Exp Psychol Anim Behav Process 5:368–378
Cain CK, Blouin AM, Barad M (2003) Temporally massed CS presentations generate more fear extinction than spaced presentations. J Exp Psychol Anim Behav Process 29:323–333
Deschaux O, Motanis H, Spennato G, Moreau JL, Garcia R (2011a) Re-emergence of extinguished auditory-cued conditioned fear following a sub-conditioning procedure: effects of hippocampal and prefrontal tetanic stimulations. Neurobiol Learn Mem 95:510–518
Deschaux O, Spennato G, Moreau JL, Garcia R (2011b) Chronic treatment with fluoxetine prevents the return of extinguished auditory-cued conditioned fear. Psychopharmacology (Berl) 215:231–237
Dirikx T, Hermans D, Vansteenwegen D, Baeyens F, Eelen P (2007) Reinstatement of conditioned responses in human differential fear conditioning. J Behav Ther Exp Psychiatry 38:237–251
Dirikx T, Vansteenwegen D, Eelen P, Hermans D (2009) Non-differential return of fear in humans after a reinstatement procedure. Acta Psychol (Amst) 130:175–182
Farrell MR, Sayed JA, Underwood AR, Wellman CL (2010) Lesion of infralimbic cortex occludes stress effects on retrieval of extinction but not fear conditioning. Neurobiol Learn Mem 94:240–246
Garcia R, Spennato G, Nilsson-Todd L, Moreau JL, Deschaux O (2008) Hippocampal low-frequency stimulation and chronic mild stress similarly disrupt fear extinction memory in rats. Neurobiol Learn Mem 89:560–566
Guest PC, Knowles MR, Molon-Noblot S, Salim K, Smith D, Murray F, Laroque P, Hunt SP, De Felipe C, Rupniak NM, McAllister G (2004) Mechanisms of action of the antidepressants fluoxetine and the substance P antagonist L-000760735 are associated with altered neurofilaments and synaptic remodeling. Brain Res 1002:1–10
Hermans D, Craske MG, Mineka S, Lovibond PF (2006) Extinction in human fear conditioning. Biol Psychiatry 60:361–368
Howland JG, Cazakoff BN (2010) Effects of acute stress and GluN2B-containing NMDA receptor antagonism on object and object-place recognition memory. Neurobiol Learn Mem 93:261–267
Izquierdo LA, Barros DM, Medina JH, Izquierdo I (2002) Stress hormones enhance retrieval of fear conditioning acquired either one day or many months before. Behav Pharmacol 13:203–213
Karpova NN, Pickenhagen A, Lindholm J, Tiraboschi E, Kulesskaya N, Agustsdottir A, Antila H, Popova D, Akamine Y, Sullivan R, Hen R, Drew LJ, Castren E (2011) Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science 334:1731–1734
Lino-de-Oliveira C, Sales AJ, Del Bel EA, Silveira MC, Guimaraes FS (2001) Effects of acute and chronic fluoxetine treatments on restraint stress-induced Fos expression. Brain Res Bull 55:747–754
Malberg JE, Duman RS (2003) Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28:1562–1571
Maroun M, Richter-Levin G (2003) Exposure to acute stress blocks the induction of long-term potentiation of the amygdala-prefrontal cortex pathway in vivo. J Neurosci 23:4406–4409
Martenyi F, Soldatenkova V (2006) Fluoxetine in the acute treatment and relapse prevention of combat-related post-traumatic stress disorder: analysis of the veteran group of a placebo-controlled, randomized clinical trial. Eur Neuropsychopharmacol 16:340–349
Merz CJ, Wolf OT, Hennig J (2010) Stress impairs retrieval of socially relevant information. Behav Neurosci 124:288–293
Meyers RA, Zavala AR, Speer CM, Neisewander JL (2006) Dorsal hippocampus inhibition disrupts acquisition and expression, but not consolidation, of cocaine conditioned place preference. Behav Neurosci 120:401–412
Miracle AD, Brace MF, Huyck KD, Singler SA, Wellman CL (2006) Chronic stress impairs recall of extinction of conditioned fear. Neurobiol Learn Mem 85:213–218
Muscat R, Papp M, Willner P (1992) Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline. Psychopharmacology (Berl) 109:433–438
Park CR, Zoladz PR, Conrad CD, Fleshner M, Diamond DM (2008) Acute predator stress impairs the consolidation and retrieval of hippocampus-dependent memory in male and female rats. Learn Mem 15:271–280
Pavlov I (1927) Conditioned reflexes. Oxford University Press, London
Quirk GJ, Garcia R, Gonzalez-Lima F (2006) Prefrontal mechanisms in extinction of conditioned fear. Biol Psychiatry 60:337–343
Rashidy-Pour A, Vafaei AA, Taherian AA, Miladi-Gorji H, Sadeghi H, Fathollahi Y, Bandegi AR (2009) Verapamil enhances acute stress or glucocorticoid-induced deficits in retrieval of long-term memory in rats. Behav Brain Res 203:76–80
Rescorla RA (2004) Spontaneous recovery. Learn Mem 11:501–509
Rescorla RA, Heth CD (1975) Reinstatement of fear to an extinguished conditioned stimulus. J Exp Psychol Anim Behav Process 1:88–96
Richardson AE, VanderKaay Tomasulo MM (2011) Influence of acute stress on spatial tasks in humans. Physiol Behav 103:459–466
Rocher C, Spedding M, Munoz C, Jay TM (2004) Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. Cereb Cortex 14:224–229
Rodriguez Manzanares PA, Isoardi NA, Carrer HF, Molina VA (2005) Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala. J Neurosci 25:8725–8734
Sandoz JC, Pham-Delegue MH (2004) Spontaneous recovery after extinction of the conditioned proboscis extension response in the honeybee. Learn Mem 11:586–597
Smeets T (2011) Acute stress impairs memory retrieval independent of time of day. Psychoneuroendocrinology 36:495–501
Spennato G, Zerbib C, Mondadori C, Garcia R (2008) Fluoxetine protects hippocampal plasticity during conditioned fear stress and prevents fear learning potentiation. Psychopharmacology (Berl) 196:583–589
Tarrier N, Sommerfield C, Pilgrim H, Humphreys L (1999) Cognitive therapy or imaginal exposure in the treatment of post-traumatic stress disorder. Twelve-month follow-up. Br J Psychiatry 175:571–575
Wilber AA, Walker AG, Southwood CJ, Farrell MR, Lin GL, Rebec GV, Wellman CL (2011) Chronic stress alters neural activity in medial prefrontal cortex during retrieval of extinction. Neuroscience 174:115–131
Acknowledgments
This study was supported by F. Hoffmann-La Roche (J.L.M), the University of Nice-Sophia Antipolis (O.D., J.L., O.N., C.C., R.G.), and The Chinese Academy of Science (X.Z.). We thank Michael Arends for reviewing the English style of the manuscript.
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Olivier Deschaux and Xigeng Zheng contributed equally to this study.
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Deschaux, O., Zheng, X., Lavigne, J. et al. Post-extinction fluoxetine treatment prevents stress-induced reemergence of extinguished fear. Psychopharmacology 225, 209–216 (2013). https://doi.org/10.1007/s00213-012-2806-x
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DOI: https://doi.org/10.1007/s00213-012-2806-x