Skip to main content Accessibility help

Selective serotonin reuptake inhibition increases noise burst-induced unconditioned and context-conditioned freezing

  • S. Melker Hagsäter (a1), Johan Thorén (a1), Robert Pettersson (a1) and Elias Eriksson (a1)



Whereas long-term administration of selective serotonin reuptake inhibitors (SSRIs) is effective for the treatment of anxiety disorders, acute administration of these drugs may exert a paradoxical anxiogenic effect. The aim of the present study was to explore the possible effect of an SSRI in situations of unconditioned or limited conditioned fear.


Male Sprague Dawley rats were administered a single dose of an SSRI, escitalopram, before acquisition or expression of context conditioned fear, where noise bursts were used as the unconditioned stimulus. Freezing was assessed as a measure of unconditioned fear (=the acute response to noise bursts) or conditioned fear (=the response to the context), respectively.


Noise bursts elicited an acute increase in freezing but no robust conditioned response 7 days after exposure. Administration of escitalopram before testing exacerbated the freezing response during presentation of the unconditioned stimulus and also unmasked a conditioned response; in contrast, administration of escitalopram prior to acquisition did not influence the conditioned response.


The data suggest that freezing in rats exposed to a stimulus inducing relatively mild fear may be enhanced by acute pretreatment with an SSRI regardless of whether the freezing displayed by the animals is an acute unconditioned response to the stimulus in question or a conditioned response to the same stimulus.


Corresponding author

Author for correspondence: S. Melker Hagsäter, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, POB 431, 405 30 Gothenburg, Sweden. Tel: +46 31 786 34 00; Fax: +46 31 786 31 64; E-mail:


Hide All
1. Borsini, F, Podhorna, J Marazziti, D (2002) Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology 163, 121141.
2. Rammsayer, T Netter, P (1990) Personality related differences in response to 5-HT uptake inhibition. Int J Neurosci 55, 99106.
3. Ramos, RT, Gentil, V Gorenstein, C (1993) Clomipramine and initial worsening in panic disorder: beyond the ‘jitteriness syndrome’. J Psychopharmacol 7, 265269.
4. 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, 483490.
5. Naslund, J, Studer, E, Petterson, R, Hagsater, M, Nilsson, S, Nissbrandt, H Eriksson, E (2015) Differences in anxiety-like behaviour within a batch of Wistar rats are associated with differences in serotonergic transmission, enhanced by acute SSRI administration and abolished by serotonin depletion. Int J Neuropsychopharmacol 18, 19.
6. Riess, BF (1945) A possible explanation of “freezing” behavior in rats. Science 102, 570.
7. Blanchard, RJ Blanchard, DC (1969) Crouching as an index of fear. J Comp Physiol Psychol 67, 370375.
8. Bolles, RC Collier, AC (1976) The effect of predictive cues on freezing in rats. Anim Learn Behav 4, 68.
9. Fanselow, MS (1980) Conditioned and unconditional components of post-shock freezing. Pavlov J Biol Sci 15, 177182.
10. Conti, LH, Maciver, CR, Ferkany, JW Abreu, ME (1990) Footshock-induced freezing behavior in rats as a model for assessing anxiolytics. Psychopharmacology 102, 492497.
11. Phillips, RG LeDoux, JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106, 274285.
12. Wallace, KJ Rosen, JB (2000) Predator odor as an unconditioned fear stimulus in rats: elicitation of freezing by trimethylthiazoline, a component of fox feces. Behav Neurosci 114, 912922.
13. Miyata, S, Shimoi, T, Hirano, S, Yamada, N, Hata, Y, Yoshikawa, N, Ohsawa, M Kamei, J (2007) Effects of serotonergic anxiolytics on the freezing behavior in the elevated open-platform test in mice. J Pharmacol Sci 105, 272278.
14. 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, 11711178.
15. 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, 11111118.
16. Hashimoto, S, Inoue, T Koyama, T (1996) Serotonin reuptake inhibitors reduce conditioned fear stress-induced freezing behavior in rats. Psychopharmacology 123, 182186.
17. 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, 121128.
18. Borelli, KG, Nobre, MJ, Brandao, ML Coimbra, NC (2004) Effects of acute and chronic fluoxetine and diazepam on freezing behavior induced by electrical stimulation of dorsolateral and lateral columns of the periaqueductal gray matter. Pharmacol Biochem Behav 77, 557566.
19. Brown, JS, Kalish, HI Farber, IE (1951) Conditioned fear as revealed by magnitude of startle response to an auditory stimulus. J Exp Psychol 41, 317328.
20. Kurtz, KH Siegel, A (1966) Conditioned fear and magnitude of startle response: a replication and extension. J Comp Physiol Psychol 62, 814.
21. Davis, M, Falls, WA, Campeau, S Kim, M (1993) Fear-potentiated startle - a neural and pharmacological analysis. Behav Brain Res 58, 175198.
22. Plappert, CF, Pilz, PK Schnitzler, HU (1993) Acoustic startle response and habituation in freezing and nonfreezing rats. Behav Neurosci 107, 981987.
23. Cranney, J (1987) Startle responding and context conditioning. Naloxone pretreatment and stimulus intensity. Pavlov J Biol Sci 22, 4751.
24. Young, BJ, Helmstetter, FJ, Rabchenuk, SA Leaton, RN (1991) Effects of systemic and intra-amygdaloid diazepam on long-term habituation of acoustic startle in rats. Pharmacol Biochem Behav 39, 903909.
25. Kiernan, M Cranney, J (1992) Immediate-startle stimulus presentation fails to condition freezing responses to contextual cues. Behav Neurosci 106, 121124.
26. Sanchez, C, Bergqvist, PB, Brennum, LT, Gupta, S, Hogg, S, Larsen, A Wiborg, O (2003) Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology 167, 353362.
27. Lugenbiel, P, Sartorius, A, Vollmayr, B Schloss, P (2010) Creatine transporter expression after antidepressant therapy in rats bred for learned helplessness. World J Biol Psychiatry 11, 329333.
28. Bagdy, G, Graf, M, Anheuer, ZE, Modos, EA Kantor, S (2001) Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635. Int J Neuropsychopharmacol 4, 399408.
29. Martin, JR, Ballard, TM Higgins, GA (2002) Influence of the 5-HT2C receptor antagonist, SB-242084, in tests of anxiety. Pharmacol Biochem Behav 71, 615625.
30. Anagnostaras, SG, Wood, SC, Shuman, T, Cai, DJ, Leduc, AD, Zurn, KR, Zurn, JB, Sage, JR Herrera, GM (2010) Automated assessment of pavlovian conditioned freezing and shock reactivity in mice using the video freeze system. Front Behav Neurosci 4(158):111.
31. Inoue, T, Kitaichi, Y Koyama, T (2011) SSRIs and conditioned fear. Prog Neuropsychopharmacol Biol Psychiatry 35, 18101819.
32. 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, 5464.
33. Pettersson, R, Naslund, J, Nilsson, S, Eriksson, E Hagsater, SM (2015) Acute escitalopram but not contextual conditioning exerts a stronger ‘anxiogenic’ effect in rats with high baseline ‘anxiety’ in the acoustic startle paradigm. Psychopharmacology 232, 14611469.
34. Burghardt, NS Bauer, EP (2013) Acute and chronic effects of selective serotonin reuptake inhibitor treatment on fear conditioning: implications for underlying fear circuits. Neuroscience 247, 253272.
35. Fuller, RW Wong, DT (1977) Inhibition of serotonin reuptake. Fed Proc 36, 21542158.
36. Gallager, DW Aghajanian, GK (1975) Effects of chlorimipramine and lysergic acid diethylamide on efflux of precursor-formed 3-H-serotonin: correlations with serotonergic impulse flow. J Pharmacol Exp Ther 193, 785795.
37. Macedo, CE, Martinez, RC, de Souza Silva, MA Brandao, ML (2005) Increases in extracellular levels of 5-HT and dopamine in the basolateral, but not in the central, nucleus of amygdala induced by aversive stimulation of the inferior colliculus. Eur J Neurosci 21, 11311138.
38. Forster, GL, Feng, N, Watt, MJ, Korzan, WJ, Mouw, NJ, Summers, CH Renner, KJ (2006) Corticotropin-releasing factor in the dorsal raphe elicits temporally distinct serotonergic responses in the limbic system in relation to fear behavior. Neuroscience 141, 10471055.
39. Yokoyama, M, Suzuki, E, Sato, T, Maruta, S, Watanabe, S Miyaoka, H (2005) Amygdalic levels of dopamine and serotonin rise upon exposure to conditioned fear stress without elevation of glutamate. Neurosci Lett 379, 3741.
40. Zanoveli, JM, Carvalho, MC, Cunha, JM Brandao, ML (2009) Extracellular serotonin level in the basolateral nucleus of the amygdala and dorsal periaqueductal gray under unconditioned and conditioned fear states: an in vivo microdialysis study. Brain Res 1294, 106115.
41. Bagdy, G, Graf, M, Anheuer, ZE, Modos, EA Kantor, S (2001) Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT(2C) receptor antagonist SB-242084 but not the 5-HT(1A) receptor antagonist WAY-100635. Int J Neuropsychopharmacol 4, 399408.
42. Yamashita, PSD, de Bortoli, VC Zangrossi, H (2011) 5-HT2C receptor regulation of defensive responses in the rat dorsal periaqueductal gray. Neuropharmacology 60, 216222.
43. Vicente, MA Zangrossi, H (2012) Serotonin-2C receptors in the basolateral nucleus of the amygdala mediate the anxiogenic effect of acute imipramine and fluoxetine administration. Int J Neuropsychopharmacol 15, 389400.
44. Marcinkiewcz, CA, Mazzone, CM, D’Agostino, G, Halladay, LR, Hardaway, JA, DiBerto, JF, Navarro, M, Burnham, N, Cristiano, C, Dorrier, CE, Tipton, GJ, Ramakrishnan, C, Kozicz, T, Deisseroth, K, Thiele, TE, McElligott, ZA, Holmes, A, Heisler, LK Kash, TL (2016) Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. Nature 537, 97101.
45. Pelrine, E, Pasik, SD, Bayat, L, Goldschmiedt, D Bauer, EP (2016) 5-HT2C receptors in the BNST are necessary for the enhancement of fear learning by selective serotonin reuptake inhibitors. Neurobiol Learn Mem 136, 189195.
46. Inoue, T, Tsuchiya, K Koyama, T (1996) Serotonergic activation reduces defensive freezing in the conditioned fear paradigm. Pharmacol Biochem Behav 53, 825831.
47. 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 12, 131143.
48. Shoji, H, Takao, K, Hattori, S Miyakawa, T (2014) Contextual and cued fear conditioning test using a video analyzing system in mice. J Vis Exp 85, e50871.


Related content

Powered by UNSILO

Selective serotonin reuptake inhibition increases noise burst-induced unconditioned and context-conditioned freezing

  • S. Melker Hagsäter (a1), Johan Thorén (a1), Robert Pettersson (a1) and Elias Eriksson (a1)


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.