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Acute escitalopram but not contextual conditioning exerts a stronger “anxiogenic” effect in rats with high baseline “anxiety” in the acoustic startle paradigm

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Abstract

Rationale

Acute administration of selective serotonin reuptake inhibitors (SSRIs) may enhance anxiety in humans, those with anxiety disorders being more susceptible than others. Fear-conditioned or unconditioned acoustic startle and freezing are common measures of fear and/or “anxiety” in rodents that may be used to study this effect of SSRIs preclinically.

Objectives

Our aim was to shed further light on the effect of acute administration of an SSRI, escitalopram (10 mg/kg), on startle and freezing in the absence or presence of prior contextual conditioning. Repeated testing also enabled us to evaluate (i) if there are stable inter-animal variations with respect to these parameters in a batch of outbred Wistar rats, (ii) the possible relationship between the two and (iii) if baseline behaviour predicts the response to escitalopram.

Results

Inter-animal test-retest correlations were found for both startle and freezing at baseline, and the two parameters also correlated with each other. Both escitalopram and contextual conditioning increased freezing and startle but without exerting any synergistic effect. While animals displaying high startle at baseline showed higher susceptibility to respond to escitalopram, the effect of conditioning was more pronounced in those with low baseline startle.

Conclusions

The results support the usefulness of both conditioned and non-conditioned startle and freezing to capture an “anxiogenic” influence of SSRIs. Also, they suggest that baseline non-conditioned startle may predict this response in a manner reflecting the clinical situation in the sense that subjects with high baseline “anxiety” are particularly prone to respond with enhanced “anxiety” following acute SSRI administration.

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References

  • Borszcz GS, Cranney J, Leaton RN (1989) Influence of long-term sensitization on long-term habituation of the acoustic startle response in rats: central gray lesions, preexposure, and extinction. J Exp Psychol Anim Behav Process 15:54–64

    Article  CAS  PubMed  Google Scholar 

  • Brandao ML, Zanoveli JM, Ruiz-Martinez RC, Oliveira LC, Landeira-Fernandez J (2008) Different patterns of freezing behavior organized in the periaqueductal gray of rats: association with different types of anxiety. Behav Brain Res 188:1–13

    Article  PubMed  Google Scholar 

  • Browning M, Reid C, Cowen PJ, Goodwin GM, Harmer CJ (2007) A single dose of citalopram increases fear recognition in healthy subjects. J Psychopharmacol 21:684–690

    Article  CAS  PubMed  Google Scholar 

  • Burghardt NS, Sullivan GM, McEwen BS, Gorman JM, LeDoux JE (2004) The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine. Biol Psychiatry 55:1171–1178

    Article  CAS  PubMed  Google Scholar 

  • Burghardt NS, Bush DE, McEwen BS, LeDoux JE (2007) Acute selective serotonin reuptake inhibitors increase conditioned fear expression: blockade with a 5-HT(2C) receptor antagonist. Biol Psychiatry 62:1111–1118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Davis M (2001) Fear-potentiated startle in rats. Curr Protoc Neurosci Chapter 8: Unit 8 11A

  • Davis M, Astrachan DI (1978) Conditioned fear and startle magnitude: effects of different footshock or backshock intensities used in training. J Exp Psychol Anim Behav Process 4:95–103

    Article  CAS  PubMed  Google Scholar 

  • Davis M, Falls WA, Campeau S, Kim M (1993) Fear-potentiated startle: a neural and pharmacological analysis. Behav Brain Res 58:175–198

    Article  CAS  PubMed  Google Scholar 

  • de Oliveira LC, Gomes MZ, Brandao ML (2011) Influence of age on reactivity to diverse emotional challenges in low- and high-anxiety rats. Int J Dev Neurosci 29:77–83

    Article  PubMed  Google Scholar 

  • Dekeyne A, Denorme B, Monneyron S, Millan MJ (2000) Citalopram reduces social interaction in rats by activation of serotonin (5-HT)(2C) receptors. Neuropharmacology 39:1114–1117

    Article  CAS  PubMed  Google Scholar 

  • Esler M, Lambert E, Alvarenga M, Socratous F, Richards J, Barton D, Pier C, Brenchley C, Dawood T, Hastings J, Guo L, Haikerwal D, Kaye D, Jennings G, Kalff V, Kelly M, Wiesner G, Lambert G (2007) Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor. Stress 10:295–304

    Article  CAS  PubMed  Google Scholar 

  • Fendt M, Fanselow MS (1999) The neuroanatomical and neurochemical basis of conditioned fear. Neurosci Biobehav Rev 23:743–760

    Article  CAS  PubMed  Google Scholar 

  • Grillon C (2002) Startle reactivity and anxiety disorders: aversive conditioning, context, and neurobiology. Biol Psychiatry 52:958–975

    Article  PubMed  Google Scholar 

  • Grillon C, Levenson J, Pine DS (2007) A single dose of the selective serotonin reuptake inhibitor citalopram exacerbates anxiety in humans: a fear-potentiated startle study. Neuropsychopharmacology 32:225–231

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto S, Inoue T, Koyama T (1996) Serotonin reuptake inhibitors reduce conditioned fear stress-induced freezing behavior in rats. Psychopharmacology 123:182–186

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto S, Inoue T, Muraki I, Koyama T (2009) Effects of acute citalopram on the expression of conditioned freezing in naive versus chronic citalopram-treated rats. Prog Neuropsychopharmacol Biol Psychiatry 33:113–117

    Article  CAS  PubMed  Google Scholar 

  • Hetem LA, de Souza CJ, Guimaraes ES, Zuardi AW, Graeff FG (1996) Effect of d-fenfluramine on human experimental anxiety. Psychopharmacology 127:276–282

    Article  CAS  PubMed  Google Scholar 

  • Inoue T, Hashimoto S, Tsuchiya K, Izumi T, Ohmori T, Koyama T (1996) Effect of citalopram, a selective serotonin reuptake inhibitor, on the acquisition of conditioned freezing. Eur J Pharmacol 311:1–6

    Article  CAS  PubMed  Google Scholar 

  • Inoue T, Li XB, Abekawa T, Kitaichi Y, Izumi T, Nakagawa S, Koyama T (2004) Selective serotonin reuptake inhibitor reduces conditioned fear through its effect in the amygdala. Eur J Pharmacol 497:311–316

    Article  CAS  PubMed  Google Scholar 

  • Kiernan M, Cranney J (1992) Immediate-startle stimulus presentation fails to condition freezing responses to contextual cues. Behav Neurosci 106:121–124

    Article  CAS  PubMed  Google Scholar 

  • Leaton RN, Borszcz GS (1985) Potentiated startle—its relation to freezing and shock-intensity in rats. J Exp Psychol Anim Behav Process 11:421–428

    Article  Google Scholar 

  • Li XB, Inoue T, Hashimoto S, Koyama T (2001) Effect of chronic administration of flesinoxan and fluvoxamine on freezing behavior induced by conditioned fear. Eur J Pharmacol 425:43–50

    Article  CAS  PubMed  Google Scholar 

  • Luyten L, Vansteenwegen D, van Kuyck K, Deckers D, Nuttin B (2011) Optimization of a contextual conditioning protocol for rats using combined measurements of startle amplitude and freezing: the effects of shock intensity and different types of conditioning. J Neurosci Methods 194:305–311

    Article  PubMed  Google Scholar 

  • Luyten L, Schroyens N, Hermans D, Beckers T (2014) Parameter optimization for automated behavior assessment: plug-and-play or trial-and-error? Front Behav Neurosci 8:28

    Article  PubMed Central  PubMed  Google Scholar 

  • Martinez RC, Ribeiro de Oliveira A, Brandao ML (2007) Serotonergic mechanisms in the basolateral amygdala differentially regulate the conditioned and unconditioned fear organized in the periaqueductal gray. Eur Neuropsychopharmacology 17:717–724

    Article  CAS  Google Scholar 

  • Matto V, Allikmets L (1999) Acute and chronic citalopram treatment differently modulates rat exploratory behavior in the exploration box test: no evidence for increased anxiety or changes in the [3H]raclopride binding. Pharmacology 58:59–69

    Article  CAS  PubMed  Google Scholar 

  • Montezinho LP, Miller S, Plath N, Jensen NH, Karlsson JJ, Witten L, Mork A (2010) The effects of acute treatment with escitalopram on the different stages of contextual fear conditioning are reversed by atomoxetine. Psychopharmacology 212:131–143

    Article  CAS  PubMed  Google Scholar 

  • Muraki I, Inoue T, Koyama T (2008) Effect of co-administration of the selective 5-HT1A receptor antagonist WAY 100,635 and selective 5-HT1B/1D receptor antagonist GR 127,935 on anxiolytic effect of citalopram in conditioned fear stress in the rat. Eur J Pharmacol 586:171–178

    Article  CAS  PubMed  Google Scholar 

  • Nishikawa H, Inoue T, Izumi T, Koyama T (2007) Synergistic effects of tandospirone and selective serotonin reuptake inhibitors on the contextual conditioned fear stress response in rats. Eur Neuropsychopharmacology 17:643–650

    Article  CAS  Google Scholar 

  • Nutt DJ, Forshall S, Bell C, Rich A, Sandford J, Nash J, Argyropoulos S (1999) Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders. Euro Neuropsychopharmacology 9(Suppl 3):S81–S86

    Article  CAS  Google Scholar 

  • Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106:274–285

    Article  CAS  PubMed  Google Scholar 

  • Plappert CF, Pilz PK, Schnitzler HU (1993) Acoustic startle response and habituation in freezing and nonfreezing rats. Behav Neurosci 107:981–987

    Article  CAS  PubMed  Google Scholar 

  • Rammsayer T, Netter P (1990) Personality related differences in response to 5-HT uptake inhibition. Int J Neurosci 55:99–106

    Article  CAS  PubMed  Google Scholar 

  • Ramos RT, Gentil V, Gorenstein C (1993) Clomipramine and initial worsening in panic disorder: beyond the ‘jitteriness syndrome’. J Psychopharmacol 7:265–269

    Article  CAS  PubMed  Google Scholar 

  • Riess BF (1945) A possible explanation of “freezing” behavior in rats. Science 102:570

    Article  CAS  PubMed  Google Scholar 

  • Santos JM, Gargaro AC, Oliveira AR, Masson S, Brandao ML (2005) Pharmacological dissociation of moderate and high contextual fear as assessed by freezing behavior and fear-potentiated startle. Eur Neuropsychopharmacology 15:239–246

    Article  CAS  Google Scholar 

  • Santos JM, Martinez RC, Brandao ML (2006) Effects of acute and subchronic treatments with fluoxetine and desipramine on the memory of fear in moderate and high-intensity contextual conditioning. Eur J Pharmacol 542:121–128

    Article  CAS  PubMed  Google Scholar 

  • Sinclair LI, Christmas DM, Hood SD, Potokar JP, Robertson A, Isaac A, Srivastava S, Nutt DJ, Davies SJ (2009) Antidepressant-induced jitteriness/anxiety syndrome: systematic review. Br J Psychiatry 194:483–490

    Article  PubMed  Google Scholar 

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Acknowledgments

Inger Oscarsson and Gunilla Bourghardt are acknowledged for excellent technical assistance. The Swedish Research Council (K2013-61X-14961-07-3), Söderberg’s Foundation (MT-30/09), Hållsten’s Foundation and the Swedish Brain Foundation (FO-20110293) are acknowledged for financial support of the research described in this report.

Conflict of interest

None of the authors declare any conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Box 431, SE-405 30, Gothenburg, Sweden

    Robert Pettersson, Jakob Näslund, Elias Eriksson & S. Melker Hagsäter

  2. Institute of Mathematical Sciences, Chalmers University of Technology, SE-412 96, Gothenburg, Sweden

    Staffan Nilsson

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  1. Robert Pettersson
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  2. Jakob Näslund
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  4. Elias Eriksson
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  5. S. Melker Hagsäter
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Correspondence to Elias Eriksson.

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Pettersson, R., Näslund, J., Nilsson, S. et al. Acute escitalopram but not contextual conditioning exerts a stronger “anxiogenic” effect in rats with high baseline “anxiety” in the acoustic startle paradigm. Psychopharmacology 232, 1461–1469 (2015). https://doi.org/10.1007/s00213-014-3783-z

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