Hostname: page-component-78c5997874-m6dg7 Total loading time: 0 Render date: 2024-11-10T17:45:06.429Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  08 November 2018

S. Melker Hagsäter Open the ORCID record for S. Melker Hagsäter [Opens in a new window] ,
Johan Thorén ,
Robert Pettersson  and
Elias Eriksson
S. Melker Hagsäter*
Affiliation:
Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Johan Thorén
Affiliation:
Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Robert Pettersson
Affiliation:
Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Elias Eriksson
Affiliation:
Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
*
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: melker.hagsater@neuro.gu.se
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

anxietydefensive behaviourserotonin
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 31 , Issue 1 , February 2019 , pp. 46 - 51
Copyright
© Scandinavian College of Neuropsychopharmacology 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Borsini, F, Podhorna, J Marazziti, D (2002) Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology 163, 121–141.Google Scholar
2. Rammsayer, T Netter, P (1990) Personality related differences in response to 5-HT uptake inhibition. Int J Neurosci 55, 99–106.Google Scholar
3. Ramos, RT, Gentil, V Gorenstein, C (1993) Clomipramine and initial worsening in panic disorder: beyond the ‘jitteriness syndrome’. J Psychopharmacol 7, 265–269.Google Scholar
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, 483–490.Google Scholar
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, 1–9.Google Scholar
6. Riess, BF (1945) A possible explanation of “freezing” behavior in rats. Science 102, 570.Google Scholar
7. Blanchard, RJ Blanchard, DC (1969) Crouching as an index of fear. J Comp Physiol Psychol 67, 370–375.Google Scholar
8. Bolles, RC Collier, AC (1976) The effect of predictive cues on freezing in rats. Anim Learn Behav 4, 6–8.Google Scholar
9. Fanselow, MS (1980) Conditioned and unconditional components of post-shock freezing. Pavlov J Biol Sci 15, 177–182.Google Scholar
10. Conti, LH, Maciver, CR, Ferkany, JW Abreu, ME (1990) Footshock-induced freezing behavior in rats as a model for assessing anxiolytics. Psychopharmacology 102, 492–497.Google Scholar
11. Phillips, RG LeDoux, JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106, 274–285.Google Scholar
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, 912–922.Google Scholar
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, 272–278.Google Scholar
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, 1171–1178.Google Scholar
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, 1111–1118.Google Scholar
16. Hashimoto, S, Inoue, T Koyama, T (1996) Serotonin reuptake inhibitors reduce conditioned fear stress-induced freezing behavior in rats. Psychopharmacology 123, 182–186.Google Scholar
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, 121–128.Google Scholar
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, 557–566.Google Scholar
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, 317–328.Google Scholar
20. Kurtz, KH Siegel, A (1966) Conditioned fear and magnitude of startle response: a replication and extension. J Comp Physiol Psychol 62, 8–14.Google Scholar
21. Davis, M, Falls, WA, Campeau, S Kim, M (1993) Fear-potentiated startle - a neural and pharmacological analysis. Behav Brain Res 58, 175–198.Google Scholar
22. Plappert, CF, Pilz, PK Schnitzler, HU (1993) Acoustic startle response and habituation in freezing and nonfreezing rats. Behav Neurosci 107, 981–987.Google Scholar
23. Cranney, J (1987) Startle responding and context conditioning. Naloxone pretreatment and stimulus intensity. Pavlov J Biol Sci 22, 47–51.Google Scholar
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, 903–909.Google Scholar
25. Kiernan, M Cranney, J (1992) Immediate-startle stimulus presentation fails to condition freezing responses to contextual cues. Behav Neurosci 106, 121–124.Google Scholar
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, 353–362.Google Scholar
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, 329–333.Google Scholar
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, 399–408.Google Scholar
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, 615–625.Google Scholar
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):1–11.Google Scholar
31. Inoue, T, Kitaichi, Y Koyama, T (2011) SSRIs and conditioned fear. Prog Neuropsychopharmacol Biol Psychiatry 35, 1810–1819.Google Scholar
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, 54–64.Google Scholar
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, 1461–1469.Google Scholar
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, 253–272.Google Scholar
35. Fuller, RW Wong, DT (1977) Inhibition of serotonin reuptake. Fed Proc 36, 2154–2158.Google Scholar
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, 785–795.Google Scholar
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, 1131–1138.Google Scholar
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, 1047–1055.Google Scholar
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, 37–41.Google Scholar
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, 106–115.Google Scholar
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, 399–408.Google Scholar
42. Yamashita, PSD, de Bortoli, VC Zangrossi, H (2011) 5-HT2C receptor regulation of defensive responses in the rat dorsal periaqueductal gray. Neuropharmacology 60, 216–222.Google Scholar
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, 389–400.Google Scholar
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, 97–101.Google Scholar
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, 189–195.Google Scholar
46. Inoue, T, Tsuchiya, K Koyama, T (1996) Serotonergic activation reduces defensive freezing in the conditioned fear paradigm. Pharmacol Biochem Behav 53, 825–831.Google Scholar
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, 131–143.Google Scholar
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.Google Scholar