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Orexin neuropeptides contribute to the development and persistence of generalized avoidance behavior in the rat

Abstract

Rationale

Avoidance of contexts directly associated with fearful experiences represents an adaptive behavioral survival strategy. Over-interpretation of contextual cues leading to generalized avoidance of situations that are only remotely similar to the original fear context represents a pathologic process that contributes to anxiety disorders. Orexin neuropeptides modulate anxiety-like behavioral and physiological responses.

Objective

The objective of this paper was to investigate the impact of pharmacological orexin receptor blockade on generalized avoidance behavior.

Methods

Rats received a single electric foot-shock in the dark side of a two-compartment shuttle box followed by situational context reminders. After shock, rats were treated chronically (3 weeks) with the orexin receptor antagonist almorexant or with the selective serotonin reuptake inhibitor sertraline, used as positive anxiolytic control. In week 3, avoidance behavior was measured under conditions of high (dark-light (DL)-box) and low (elevated plus maze (EPM)) similarity to the original shock context. Avoidance behavior was re-assessed 5 and 17 weeks after treatment termination.

Results

Avoidance in the DL box (contextual fear memory) remained unaffected by any treatment and lasted 20 weeks post-shock exposure. Avoidance in the EPM (neophobic fear generalization) was partially attenuated during treatment with almorexant and sertraline at week 3. Following 5 and 17 weeks of drug washout, avoidance in the EPM was significantly reduced in almorexant- but not in sertraline-treated rats. Almorexant also reduced persistent avoidance in the EPM upon treatment initiation 3 weeks after shock exposure.

Conclusion

Chronic orexin receptor blockade in rats reduces both the development and persistence of generalized avoidance in situations with low similarity to the initial shock context.

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References

  • Bettica P, Nucci G, Pyke C, Squassante L, Zamuner S, Ratti E, Gomeni R, Alexander R (2012) Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist. J Psychopharmacol 26:1058–1070

    Article  CAS  PubMed  Google Scholar 

  • Biedenkapp JC, Rudy JW (2007) Context preexposure prevents forgetting of a contextual fear memory: implication for regional changes in brain activation patterns associated with recent and remote memory tests. Learn Mem 14:200–203

    Article  PubMed Central  PubMed  Google Scholar 

  • Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, van Gerven J, de Haas SL, Hess P, Qiu C, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13:150–155

    Article  CAS  PubMed  Google Scholar 

  • Cano G, Mochizuki T, Saper CB (2008) Neural circuitry of stress-induced insomnia in rats. J Neurosci 28:10167–10184

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen X, Wang H, Lin Z, Li S, Li Y, Bergen HT, Vrontakis ME, Kirouac GJ (2013) Orexins (hypocretins) contribute to fear and avoidance in rats exposed to a single episode of footshocks. Brain Struct Funct. doi:10.1007/s00429-013-0626-3

  • Cluderay JE, Harrison DC, Hervieu GJ (2002) Protein distribution of the orexin-2 receptor in the rat central nervous system. Regul Pept 104:131–144

    Article  CAS  PubMed  Google Scholar 

  • Cryan JF, Valentino RJ, Lucki I (2005) Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 29:547–569

    Article  CAS  PubMed  Google Scholar 

  • Dietrich H, Jenck F (2010) Intact learning and memory in rats following treatment with the dual orexin receptor antagonist almorexant. Psychopharmacology (Berlin) 212:145–154

    Article  CAS  Google Scholar 

  • Duvarci S, Bauer EP, Pare D (2009) The bed nucleus of the stria terminalis mediates inter-individual variations in anxiety and fear. J Neurosci 29:10357–10361

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dymond S, Schlund MW, Roche B, De Houwer J, Freegard GP (2012) Safe from harm: learned, instructed, and symbolic generalization pathways of human threat-avoidance. PLoS One 7:e47539

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Flores A, Valls-Comamala V, Costa G, Saravia R, Maldonado R, Berrendero F (2014) The hypocretin/orexin system mediates the extinction of fear memories. Neuropsychopharmacology. doi:10.1038/npp.2014.146

  • Furlong TM, Vianna DM, Liu L, Carrive P (2009) Hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal. Eur J Neurosci 30:1603–1614

    Article  PubMed  Google Scholar 

  • Graves LA, Heller EA, Pack AI, Abel T (2003) Sleep deprivation selectively impairs memory consolidation for contextual fear conditioning. Learn Mem 10:168–176

    Article  PubMed Central  PubMed  Google Scholar 

  • Handley SL, Mithani S (1984) Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of ‘fear’-motivated behaviour. Naunyn Schmiedeberg’s Arch Pharmacol 327:1–5

    Article  CAS  Google Scholar 

  • Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA (2001) Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 103:777–797

    Article  CAS  PubMed  Google Scholar 

  • Hiemke C, Hartter S (2000) Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther 85:11–28

    Article  CAS  PubMed  Google Scholar 

  • Hoever P, Dorffner G, Benes H, Penzel T, Danker-Hopfe H, Barbanoj MJ, Pillar G, Saletu B, Polo O, Kunz D, Zeitlhofer J, Berg S, Partinen M, Bassetti CL, Hogl B, Ebrahim IO, Holsboer-Trachsler E, Bengtsson H, Peker Y, Hemmeter UM, Chiossi E, Hajak G, Dingemanse J (2012) Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial. Clin Pharmacol Ther 91:975–985

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ipser J, Seedat S, Stein DJ (2006) Pharmacotherapy for post-traumatic stress disorder—a systematic review and meta-analysis. S Afr Med J 96:1088–1096

    CAS  PubMed  Google Scholar 

  • Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S, Traskman-Bendz L, Goddard AW, Brundin L, Shekhar A (2010) A key role for orexin in panic anxiety. Nat Med 16:111–115

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Johnson PL, Samuels BC, Fitz SD, Lightman SL, Lowry CA, Shekhar A (2012) Activation of the orexin 1 receptor is a critical component of CO2-mediated anxiety and hypertension but not bradycardia. Neuropsychopharmacology 37:1911–1922

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kaouane N, Porte Y, Vallee M, Brayda-Bruno L, Mons N, Calandreau L, Marighetto A, Piazza PV, Desmedt A (2012) Glucocorticoids can induce PTSD-like memory impairments in mice. Science 335:1510–1513

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Li S, Wei C, Wang H, Sui N, Kirouac GJ (2010) Orexins in the paraventricular nucleus of the thalamus mediate anxiety-like responses in rats. Psychopharmacology (Berlin) 212:251–265

    Article  CAS  Google Scholar 

  • Louvart H, Maccari S, Lesage J, Leonhardt M, Dickes-Coopman A, Darnaudery M (2006) Effects of a single footshock followed by situational reminders on HPA axis and behaviour in the aversive context in male and female rats. Psychoneuroendocrinology 31:92–99

    Article  CAS  PubMed  Google Scholar 

  • Lungwitz EA, Molosh A, Johnson PL, Harvey BP, Dirks RC, Dietrich A, Minick P, Shekhar A, Truitt WA (2012) Orexin-A induces anxiety-like behavior through interactions with glutamatergic receptors in the bed nucleus of the stria terminalis of rats. Physiol Behav 107:726–732

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maren S, Phan KL, Liberzon I (2013) The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci 14:417–428

    Article  CAS  PubMed  Google Scholar 

  • Morairty SR, Revel FG, Malherbe P, Moreau JL, Valladao D, Wettstein JG, Kilduff TS, Borroni E (2012) Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone. PLoS One 7:e39131

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Myers CE, Vanmeenen KM, Servatius RJ (2012) Behavioral inhibition and PTSD symptoms in veterans. Psychiatry Res 196:271–276

    Article  PubMed Central  PubMed  Google Scholar 

  • Nollet M, Gaillard P, Tanti A, Girault V, Belzung C, Leman S (2012) Neurogenesis-independent antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression. Neuropsychopharmacology 37:2210–2221

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • North CS, Nixon SJ, Shariat S, Mallonee S, McMillen JC, Spitznagel EL, Smith EM (1999) Psychiatric disorders among survivors of the Oklahoma City bombing. JAMA 282:755–762

    Article  CAS  PubMed  Google Scholar 

  • Olson VG, Rockett HR, Reh RK, Redila VA, Tran PM, Venkov HA, Defino MC, Hague C, Peskind ER, Szot P, Raskind MA (2011) The role of norepinephrine in differential response to stress in an animal model of posttraumatic stress disorder. Biol Psychiatry 70:441–448

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Oyarzun JP, Packard PA (2012) Stress-induced gist-based memory processing: a possible explanation for overgeneralization of fear in posttraumatic stress disorder. J Neurosci 32:9771–9772

    Article  CAS  PubMed  Google Scholar 

  • Pamplona FA, Henes K, Micale V, Mauch CP, Takahashi RN, Wotjak CT (2011) Prolonged fear incubation leads to generalized avoidance behavior in mice. J Psychiatr Res 45:354–360

    Article  CAS  PubMed  Google Scholar 

  • Panahi Y, Moghaddam BR, Sahebkar A, Nazari MA, Beiraghdar F, Karami G, Saadat AR (2011) A randomized, double-blind, placebo-controlled trial on the efficacy and tolerability of sertraline in Iranian veterans with post-traumatic stress disorder. Psychol Med 41:2159–2166

    Article  CAS  PubMed  Google Scholar 

  • Pynoos RS, Ritzmann RF, Steinberg AM, Goenjian A, Prisecaru I (1996) A behavioral animal model of posttraumatic stress disorder featuring repeated exposure to situational reminders. Biol Psychiatry 39:129–134

    Article  CAS  PubMed  Google Scholar 

  • Radulovic J, Kammermeier J, Spiess J (1998) Generalization of fear responses in C57BL/6N mice subjected to one-trial foreground contextual fear conditioning. Behav Brain Res 95:179–189

    Article  CAS  PubMed  Google Scholar 

  • Rodgers RJ, Shepherd JK (1993) Influence of prior maze experience on behaviour and response to diazepam in the elevated plus-maze and light/dark tests of anxiety in mice. Psychopharmacology (Berlin) 113:237–242

    Article  CAS  Google Scholar 

  • Rolls A, Colas D, Adamantidis A, Carter M, Lanre-Amos T, Heller HC, de Lecea L (2011) Optogenetic disruption of sleep continuity impairs memory consolidation. Proc Natl Acad Sci U S A 108:13305–13310

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ruskin DN, Liu C, Dunn KE, Bazan NG, LaHoste GJ (2004) Sleep deprivation impairs hippocampus-mediated contextual learning but not amygdala-mediated cued learning in rats. Eur J Neurosci 19:3121–3124

    Article  PubMed  Google Scholar 

  • Sakurai T, Mieda M, Tsujino N (2010) The orexin system: roles in sleep/wake regulation. Ann N Y Acad Sci 1200:149–161

    Article  CAS  PubMed  Google Scholar 

  • Sauerhofer E, Pamplona FA, Bedenk B, Moll GH, Dawirs RR, von Horsten S, Wotjak CT, Golub Y (2012) Generalization of contextual fear depends on associative rather than non-associative memory components. Behav Brain Res 233:483–493

    Article  PubMed  Google Scholar 

  • Schmitt O, Usunoff KG, Lazarov NE, Itzev DE, Eipert P, Rolfs A, Wree A (2012) Orexinergic innervation of the extended amygdala and basal ganglia in the rat. Brain Struct Funct 217:233–256

    Article  CAS  PubMed  Google Scholar 

  • Scott MM, Marcus JN, Pettersen A, Birnbaum SG, Mochizuki T, Scammell TE, Nestler EJ, Elmquist JK, Lutter M (2011) Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behav Brain Res 222:289–294

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sears RM, Fink AE, Wigestrand MB, Farb CR, de Lecea L, Ledoux JE (2013) Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Proc Natl Acad Sci U S A 110:20260–20265

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Solomon Z, Horesh D, Ein-Dor T (2009) The longitudinal course of posttraumatic stress disorder symptom clusters among war veterans. J Clin Psychiatry 70:837–843

    Article  PubMed  Google Scholar 

  • Soya S, Shoji H, Hasegawa E, Hondo M, Miyakawa T, Yanagisawa M, Mieda M, Sakurai T (2013) Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory consolidation. J Neurosci 33:14549–14557

    Article  CAS  PubMed  Google Scholar 

  • Steiner MA, Lecourt H, Jenck F (2012) The brain orexin system and almorexant in fear-conditioned startle reactions in the rat. Psychopharmacology (Berlin) 223:465–475

    Article  CAS  Google Scholar 

  • Tang X, Yang L, Sanford LD (2005) Rat strain differences in freezing and sleep alterations associated with contextual fear. Sleep 28:1235–1244

    PubMed  Google Scholar 

  • van der Helm E, Yao J, Dutt S, Rao V, Saletin JM, Walker MP (2011) REM sleep depotentiates amygdala activity to previous emotional experiences. Curr Biol 21:2029–2032

    Article  PubMed Central  PubMed  Google Scholar 

  • van der Kolk BA (2006) Clinical implications of neuroscience research in PTSD. Ann N Y Acad Sci 1071:277–293

    Article  PubMed  Google Scholar 

  • Viviani D, Haegler P, Strasser DS, Steiner MA (2012) Sex comparison on long-lasting behavioral and physiological disturbances induced by single shock experience in rats. Physiol Behav 107:243–251

    Article  CAS  PubMed  Google Scholar 

  • Walling SG, Nutt DJ, Lalies MD, Harley CW (2004) Orexin-A infusion in the locus ceruleus triggers norepinephrine (NE) release and NE-induced long-term potentiation in the dentate gyrus. J Neurosci 24:7421–7426

    Article  CAS  PubMed  Google Scholar 

  • Wiltgen BJ, Silva AJ (2007) Memory for context becomes less specific with time. Learn Mem 14:313–317

    Article  PubMed  Google Scholar 

  • Winrow CJ, Gotter AL, Cox CD, Doran SM, Tannenbaum PL, Breslin MJ, Garson SL, Fox SV, Harrell CM, Stevens J, Reiss DR, Cui D, Coleman PJ, Renger JJ (2011) Promotion of sleep by suvorexant—a novel dual orexin receptor antagonist. J Neurogenet 25:52–61

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Rebekka Pietrek, Cedric Fischer, and Malvina Louis (all Actelion Pharmaceuticals) for their excellent technical assistance, Carla Sciarretta (Actelion) for valuable suggestions on the manuscript, and Catherine Brisbare-Roch (Actelion) and Jed Black (Stanford) for conceptual contributions.

Conflict of interest

All authors were employees of Actelion Pharmaceuticals Ltd. at the time the study was conducted. They have no other financial conflicts of interest to declare.

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Correspondence to Michel A. Steiner.

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Viviani, D., Haegler, P., Jenck, F. et al. Orexin neuropeptides contribute to the development and persistence of generalized avoidance behavior in the rat. Psychopharmacology 232, 1383–1393 (2015). https://doi.org/10.1007/s00213-014-3769-x

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  • DOI: https://doi.org/10.1007/s00213-014-3769-x

Keywords

  • Almorexant
  • Sertraline
  • Orexin
  • Rat
  • Avoidance
  • Neuroscience
  • Pharmacology
  • Orexin receptor antagonist
  • Fear
  • Neuropeptide