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5‐HT depletion, but not 5‐HT1A antagonist, prevents the anxiolytic‐like effect of citalopram in rat contextual conditioned fear stress model

  • Takahiro Masuda (a1), Hiroyuki Nishikawa (a1), Takeshi Inoue (a1), Hiroyuki Toda (a1), Shin Nakagawa (a1), Shuken Boku (a1) and Tsukasa Koyama (a1)...
Abstract
Objective

Selective serotonin reuptake inhibitors (SSRIs) have been widely used in the treatment of most anxiety disorders. In this study, to clarify the mechanism of the anxiolytic effect, we investigated the mechanism underlying the effect of the SSRI citalopram on rat contextual conditioned fear stress (CFS), an animal model of anxiety.

Methods

Rats individually received footshocks in a shock chamber. More than 1 day later, they were given citalopram and/or dlp‐chlorophenylalanine (PCPA), various subtype‐selective serotonin (5‐HT) receptor antagonists: the 5‐HT1A receptor antagonist WAY 100635, the 5‐HT2A receptor antagonist MDL 100907, the 5‐HT2C receptor antagonist SB 242084, the 5‐HT3 receptor antagonist tropisetron, the 5‐HT4 receptor antagonist GR 125487, the 5‐HT6 receptor antagonist SB 258585 or the 5‐HT7 receptor antagonist SB 269970. After drug administration, freezing behaviour, which was used as an index of anxiety, was analysed in the same shock chamber without shocks.

Results

Citalopram dose dependently reduced conditioned freezing behaviour. The anxiolytic‐like effect of citalopram was prevented completely by pretreatment with the 5‐HT‐depleting agent PCPA, but not by the 5‐HT1A receptor antagonist WAY 100635. Furthermore, none of the subtype‐selective 5‐HT receptor antagonists significantly affected conditioned freezing or affected the anxiolytic‐like effect of citalopram.

Conclusion

The anxiolytic‐like effect of citalopram in contextual CFS model depends on 5‐HT availability. In addition, contextual CFS model is suggested to be completely different from conventional anxiety models in neural mechanism or manners of serotonergic involvement. However, further studies are needed to identify the pharmacological mechanisms responsible for the anxiolytic‐like effect of citalopram.

Copyright
Corresponding author
Takeshi Inoue, Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo 060–8638, Japan. Tel: +81‐11‐706‐5160; Fax: +81‐11‐706‐5081; E‐mail: tinoue@med.hokudai.ac.jp
References
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1Zohar, J, Westenberg, HGM. Anxiety disorders: a review of tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta Psychiatr Scand 2000;101(Suppl. 403):3949.
2Nutt, DJ. Overview of diagnosis and drug treatments of anxiety disorders. CNS Spectr 2005;10:4956.
3Bandelow, B, Zohar, J, Hollander, E, Kasper, S, Möller, HJ. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive‐compulsive and post‐traumatic stress disorders – first revision. World J Biol Psychiatry 2008;9:248312.
4Fuller, RW. Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis. Life Sci 1994;55:163167.
5Gavioli, EC, Vaughan, CW, Marzola, G et al. Antidepressant‐like effects of the nociceptin/orphanin FQ receptor antagonist UFP‐101: new evidence from rats and mice. Naunyn Schmiedebergs Arch Pharmacol 2004;369:547553.
6O'leary, OF, Bechtholt, AJ, Crowley, JJ, Hill, TE, Page, ME, Lucki, I. Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test. Psychopharmacology (Berl) 2007;192:357371.
7Hoyer, D, Hannon, JP, Martin, GR. Molecular, pharmacological and functional diversity of 5‐HT receptors. Pharmacol Biochem Behav 2002;71:533554.
8Feighner, JP, Merideth, CH, Hendrickson, GA. A double‐blind comparison of buspirone and diazepam in outpatients with generalized anxiety disorder. J Clin Psychiatry 1982;43:103108.
9Borsini, F, Podhorna, J, Marazziti, D. Do animal models of anxiety predict anxiolytic‐like effects of antidepressants? Psychopharmacology (Berl) 2002;163:121141.
10Hashimoto, S, Inoue, T, Koyama, T. Serotonin reuptake inhibitors reduce conditioned fear stress‐induced freezing behavior in rats. Psychopharmacology (Berl) 1996;123:182186.
11Inoue, T, Tsuchiya, K, Koyama, T. Serotonergic activation reduces defensive freezing in the conditioned fear paradigm. Pharmacol Biochem Behav 1996;53:825831.
12Inoue, T, Li, XB, Abekawa, T et al. Selective serotonin reuptake inhibitor reduces conditioned fear through its effect in the amygdala. Eur J Pharmacol 2004;497:311316.
13Nishikawa, H, Inoue, T, Izumi, T, Koyama, T. Synergistic effects of tandospirone and selective serotonin reuptake inhibitors on the contextual conditioned fear stress response in rats. Eur Neuropsychopharmacol 2007;17:643650.
14Sanchez, C, Hytell, J. Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 1999;19:467489.
15Pozzi, L, Invernizzi, R, Garavaglia, C, Samanin, R. Fluoxetine increases extracellular dopamine in the prefrontal cortex by a mechanism not dependent on serotonin: a comparison with citalopram. J Neurochem 1999;73:10511057.
16Yoshioka, M, Matsumoto, M, Togashi, H, Saito, H. Effects of conditioned fear stress on 5‐HT release in the rat prefrontal cortex. Pharmacol Biochem Behav 1995;51:515519.
17Letty, S, Child, R, Dumuis, A, Pantaloni, A, Bockaert, J, Rondouin, G. 5‐HT4 receptors improve social olfactory memory in the rat. Neuropharmacology 1997;36:681687.
18Schreiber, R, Melon, C, de Vry, J. The role of 5‐HT receptor subtypes in the anxiolytic effects of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test. Psychopharmacology (Berl) 1998;135:383391.
19Martin, JR, Ballard, TM, Higgins, GA. Influence of the 5‐HT2C receptor antagonist, SB‐242084, in tests of anxiety. Pharmacol Biochem Behav 2002;71:615625.
20Harasawa, T, Ago, Y, Itoh, S, Baba, A, Matsuda, T. Role of serotonin type 1A receptors in fluvoxamine‐induced inhibition of marble‐burying behavior in mice. Behav Pharmacol 2006;17:637640.
21Mitchell, ES, Sexton, T, Neumaier, JF. Increased expression of 5‐HT6 receptors in the rat dorsomedial striatum impairs instrumental learning. Neuropsychopharmacology 2006;32:15201530.
22Wesolowska, A, Nikiforuk, A, Stachowicz, K, Tatarczynska, E. Effect of the selective 5‐HT7 receptor antagonist SB 269970 in animal models of anxiety and depression. Neuropharmacology 2006;51:578586.
23Muraki, I, Inoue, T, Koyama, T. 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 2008;586:171178.
24File, SE, Hyde, JR. The effects of p‐chlorophenylalanine and ethanolamine‐O‐sulphate in an animal test of anxiety. J Pharm Pharmacol 1977;29:735738.
25Söderpalm, B, Engel, JA. Does the PCPA induced anticonflict effect involve activation of the GABAA/benzodiazepine chloride ionophore receptor complex? J Neural Transm 1989;76:145153.
26Kshama, D, Hrishikeshavan, HJ, Shanbhogue, R, Munonyedi, US. Modulation of baseline behavior in rats by putative serotonergic agents in three ethoexperimental paradigms. Behav Neural Biol 1990;54:234253.
27Hashimoto, S, Inoue, T, Koyama, T. Effects of conditioned fear stress on serotonin neurotransmission and freezing behavior in rats. Eur J Pharmacol 1999;378:2330.
28Nutt, DJ, Forshall, S, Bell, C, Rich, A et al. Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders. Eur Neuropsychopharmacol 1999;9(suppl. 3):S81S86.
29Argyropoulos, SV, Hood, SD, Adrover, M et al. Tryptophan depletion reverses the therapeutic effect of selective serotonin reuptake inhibitors in social anxiety disorder. Biol Psychiatry 2004;56:503509.
30Pyle, AC, Argyropoulos, SV, Nutt, DJ. The role of serotonin in panic: evidence from tryptophan depletion studies. Acta Neuropsychiatr 2004;16:7984.
31Li, XB, Inoue, T, Abekawa, T et al. 5‐HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5‐HT1A receptors in the hippocampus and amygdala. Eur J Pharmacol 2006;532:7480.
32Romero, L, Ildefonso, H, Artigas, F. The 5‐HT1A antagonist WAY 100635 selectively potentiates the presynaptic effects of serotonergic antidepressants in rat brain. Neurosci Lett 1996;219:123126.
33Schreiber, R, de Vry, J. Neuronal circuits involved in the anxiolytic effects of the 5‐HT1A receptor agonists 8‐OH‐DPAT ipsapirone and buspirone in the rat. Eur J Pharmacol 1993;249:341351.
34Burghardt, NS, Bush, DE, Mcewen, BS, Ledoux, JE. Acute selective serotonin reuptake inhibitors increase conditioned fear expression: blockade with a 5‐HT2C receptor antagonist. Biol Psychiatry 2007;62:11111118.
35Ledoux, JE. The amygdala and emotion: a view through fear. In: Aggleton, JP, eds. The amygdala: a functional analysis, 2nd edn. Oxford University Press, Oxford, 2000.
36Silvestre, JS, Fernández, AG, Palacios, JM. Effects of 5‐HT4 receptor antagonists on rat behaviour in the elevated plus‐maze test. Eur J Pharmacol 1996;309:219222.
37Olivier, B, van Wijngaarden, I, Soudijn, W. 5‐HT3 receptor antagonists and anxiety: a preclinical and clinical review. Eur Neuropsychopharmacol 2000;10:7795.
38Wesolwska, A, Nikiforuk, A, Stachowicz, K. Anxiolytic‐like and antidepressant‐like effects produced by the selective 5‐HT6 receptor antagonist SB‐258585 after intrahippocampal administration to rats. Behav Pharmacol 2007;18:439446.
39Bai, F, Yin, T, Johnstone, EM et al. Molecular cloning and pharmacological characterization of the guinea pig 5‐HT1E receptor. Eur J Pharmacol 2004;484:127139.
40Li, XB, Inoue, T, Hashimoto, S, Koyama, T. Effect of chronic administration of flesinoxan and fluvoxamine on freezing behavior induced by conditioned fear. Eur J Pharmacol 2001;425:4350.
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Acta Neuropsychiatrica
  • ISSN: 0924-2708
  • EISSN: 1601-5215
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