Hostname: page-component-78c5997874-v9fdk Total loading time: 0 Render date: 2024-11-05T19:38:55.865Z Has data issue: false hasContentIssue false
  • English
  • Français

Asenapine reduces anxiety-related behaviours in rat conditioned fear stress model

Published online by Cambridge University Press:  21 April 2016

Masayo Ohyama ,
Maho Kondo ,
Miki Yamauchi ,
Taiichiro Imanishi  and
Tsukasa Koyama
Masayo Ohyama*
Affiliation:
Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Kohoku-ku, Yokohama, Japan
Maho Kondo
Affiliation:
Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Kohoku-ku, Yokohama, Japan
Miki Yamauchi
Affiliation:
Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Kohoku-ku, Yokohama, Japan
Taiichiro Imanishi
Affiliation:
Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Kohoku-ku, Yokohama, Japan
Tsukasa Koyama
Affiliation:
Ohyachi Hospital, Clinical Research Center, Atsubetsu, Sapporo, Japan
*
Masayo Ohyama, Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. Tel: +81(45) 541 2521; Fax: +81(45) 541 1768; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective

Asenapine is an atypical antipsychotic that is currently available for the treatment of schizophrenia and bipolar I disorder. Although the atypical antipsychotics clozapine and olanzapine are effective for depression and anxiety in schizophrenia, as demonstrated by animal model studies, this has not been clarified for asenapine. Therefore, we compared the effects of asenapine in the conditioned fear stress model with those of clozapine and olanzapine.

Method

Rats were individually fear conditioned using electrical foot shock in a Skinner box. Approximately 24 h later, individual animals were returned to the same Skinner box (without electrical shock) and their freezing behaviour was observed for 5 min. Animals were treated with asenapine, clozapine, olanzapine, the 5-HT1A receptor partial agonist buspirone, or the 5-HT2C receptor antagonist SB242084 at 30 min before freezing behaviour assessment. The 5-HT1A receptor antagonist WAY100635 or the 5-HT2C receptor agonist Ro60-0175 was also used concomitantly with asenapine. The effects of asenapine, clozapine, and olanzapine on serotonin release in the rat hippocampus were also measured using in vivo microdialysis.

Results

Asenapine reduced freezing behaviour, while neither clozapine nor olanzapine reduced freezing behaviour. Buspirone and SB242084 also reduced freezing behaviour. The effect of asenapine in reducing freezing behaviour was not altered by the concomitant administration of WAY100635 or Ro60-0175. Both asenapine and clozapine, but not olanzapine, increased serotonin release in the rat hippocampus.

Conclusion

Asenapine may have superior therapeutic effect on anxiety symptoms than other agents, although the underlying mechanism of its anxiolytic activity remains unknown.

Keywords

anxietyasenapineclozapineconditioned fear stressolanzapine
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 28 , Issue 6 , December 2016 , pp. 327 - 336
Check for updates
Copyright
© Scandinavian College of Neuropsychopharmacology 2016 

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. Tollefson, GD, Sanger, TM, Beasley, CM, Tran, PV. A double-blind, controlled comparison of the novel antipsychotic olanzapine versus haloperidol or placebo on anxious and depressive symptoms accompanying schizophrenia. Biol Psychiatry 1998;43:803–810.CrossRefGoogle ScholarPubMed
2. Davis, JM, Chen, N. The effects of olanzapine on the 5 dimensions of schizophrenia derived by factor analysis: combined results of the North American and international trials. J Clin Psychiatry 2001;62:757–771.CrossRefGoogle ScholarPubMed
3. Tohen, M, Vieta, E, Calabrese, J et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60:1079–1088.CrossRefGoogle ScholarPubMed
4. Stein, MB, Kline, NA, Matloff, JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: a double-blind, placebo-controlled study. Am J Psychiatry 2002;159:1777–1779.CrossRefGoogle ScholarPubMed
5. Barnett, SD, Kramer, ML, Casat, CD, Connor, KM, Davidson, JR. Efficacy of olanzapine in social anxiety disorder: a pilot study. J Psychopharmacol 2002;16:365–368.CrossRefGoogle ScholarPubMed
6. Kane, JM, Marder, SR, Schooler, NR et al. Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison. Arch Gen Psychiatry 2001;58:965–972.CrossRefGoogle ScholarPubMed
7. Corbett, R, Hartman, H, Kerman, LL et al. Effects of atypical antipsychotic agents on social behavior in rodents. Pharmacol Biochem Behav 1993;45:9–17.CrossRefGoogle ScholarPubMed
8. Frye, CA, Seliga, AM. Olanzapine’s effects to reduce fear and anxiety and enhance social interactions coincide with increased progestin concentrations of ovariectomized rats. Psychoneuroendocrinology 2003;28:657–673.CrossRefGoogle ScholarPubMed
9. Rogóż, Z, Skuza, G. Anxiolytic-like effects of olanzapine, risperidone and fluoxetine in the elevated plus-maze test in rats. Pharmacol Rep 2011;63:1547–1552.CrossRefGoogle ScholarPubMed
10. Szewczak, MR, Corbett, R, Rush, DK et al. The pharmacological profile of iloperidone, a novel atypical antipsychotic agent. J Pharmacol Exp Ther 1995;274:1404–1413.Google ScholarPubMed
11. Coward, DM, Imperato, A, Urwyler, S, White, TG. Biochemical and behavioural properties of clozapine. Psychopharmacology (Ber) 1989;99:S6–S12.CrossRefGoogle ScholarPubMed
12. Bymaster, FP, Calligaro, DO, Falcone, JF et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996;14:89–96.CrossRefGoogle ScholarPubMed
13. Peroutka, SJ. 5-HT receptors: past, present and future. Trends Neurosci 1995;18:68–69.CrossRefGoogle ScholarPubMed
14. Jones, BJ, Blackburn, TP. The medical benefit of 5-HT research. Pharmacol Biochem Behav 2002;71:555–568.CrossRefGoogle ScholarPubMed
15. Schotte, A, Janssen, PF, Gommeren, W et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 1996;124:57–73.CrossRefGoogle ScholarPubMed
16. Shahid, M, Walker, GB, Zorn, SH, Wong, EH. Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. J Psychopharmacol 2009;23:65–73.CrossRefGoogle ScholarPubMed
17. Ghanbari, R, El Mansari, M, Shahid, M, Blier, P. Electrophysiological characterization of the effects of asenapine at 5-HT1A, 5-HT2A, α2-adrenergic and D2 receptors in the rat brain. Eur Neuropsychopharmacol 2009;19:177–187.CrossRefGoogle Scholar
18. Potkin, SG, Cohen, M, Panagides, J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. J Clin Psychiatry 2007;68:1492–1500.CrossRefGoogle ScholarPubMed
19. Szegedi, A, Zhao, J, van Willigenburg, A, Nations, KR, Mackle, M, Panagides, J. Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials. BMC Psychiatry 2011;11:101.CrossRefGoogle ScholarPubMed
20. Samalin, L, Charpeaud, T, Llorca, PM. Asenapine in bipolar I disorder: evidence and place in patient management. Ther Adv Chronic Dis 2013;4:5–14.CrossRefGoogle ScholarPubMed
21. Fanselow, MS, Helmstetter, FJ. Conditional analgesia, defensive freezing, and benzodiazepines. Behav Neurosci 1988;102:233–243.CrossRefGoogle ScholarPubMed
22. Inoue, T, Tsuchiya, K, Koyama, T. Serotonergic activation reduces defensive freezing in the conditioned fear paradigm. Pharmacol Biochem Behav 1996;53:825–831.CrossRefGoogle ScholarPubMed
23. Inoue, T, Hashimoto, S, Tsuchiya, K, Izumi, T, Ohmori, T, Koyama, T. Effect of citalopram, a selective serotonin reuptake inhibitor, on the acquisition of conditioned freezing. Eur J Pharmacol 1996;311:1–6.CrossRefGoogle ScholarPubMed
24. Rittenhouse, PA, Bakkum, EA, O’Connor, PA, Carnes, M, Bethea, CL, van de Kar, LD. Comparison of neuroendocrine and behavioral effects of ipsapirone, a 5-HT1A agonist, in three stress paradigms: immobilization, forced swim and conditioned fear. Brain Res 1992;580:205–214.CrossRefGoogle Scholar
25. Li, X, 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;532:74–80.CrossRefGoogle ScholarPubMed
26. Pixinos, G, Watson, C. The rat brain in stereotaxic coordinates, 2nd edn. San Diego: Academic Press, 1986.Google Scholar
27. Costall, B, Domeney, AM, Kelly, ME, Naylor, RJ, Tomkins, DM. Actions of ORG 5222 as a novel psychotropic agent. Pharmacol Biochem Behav 1990;35:607–615.CrossRefGoogle ScholarPubMed
28. Marston, HM, Martin, FD, Papp, M, Gold, L, Wong, EH, Shahid, M. Attenuation of chronic mild stress-induced ‘anhedonia’ by asenapine is not associated with a ‘hedonic’ profile in intracranial self-stimulation. J Psychopharmacol 2011;25:1388–1398.CrossRefGoogle Scholar
29. Frånberg, O, Wiker, C, Marcus, MM et al. Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia. Psychopharmacology (Berl) 2008;196:417–429.CrossRefGoogle ScholarPubMed
30. Ene, HM, Kara, NZ, Barak, N, Reshef Ben-Mordechai, T, Einat, H. Effects of repeated asenapine in a battery of tests for anxiety-like behaviours in mice. Acta Neuropsychiatr 2015;11:1–7.Google Scholar
31. Inoue, T, Tsuchiya, K, Koyama, T. Effects of typical and atypical antipsychotic drugs on freezing behavior induced by conditioned fear. Pharmacol Biochem Behav 1996;55:195–201.CrossRefGoogle ScholarPubMed
32. Ishida-Tokuda, K, Ohno, Y, Sakamoto, H et al. Evaluation of perospirone (SM-9018), a novel serotonin-2 and dopamine-2 receptor antagonist, and other antipsychotics in the conditioned fear stress-induced freezing behavior model in rats. Jpn J Pharmacol 1996;72:119–126.CrossRefGoogle ScholarPubMed
33. Mead, A, Li, M, Kapur, S. Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: contrast with haloperidol and chlordiazepoxide. Pharmacol Biochem Behav 2008;90:551–562.CrossRefGoogle ScholarPubMed
34. Sun, T, He, W, Hu, G, Li, M. Anxiolytic-like property of risperidone and olanzapine as examined in multiple measures of fear in rats. Pharmacol Biochem Behav 2010;95:298–307.CrossRefGoogle ScholarPubMed
35. Kołaczkowski, M, Mierzejewski, P, Bienkowski, P, Wesołowska, A, Newman-Tancredi, A. Antipsychotic, antidepressant, and cognitive-impairment properties of antipsychotics: rat profile and implications for behavioral and psychological symptoms of dementia. Naunyn Schmiedebergs Arch Pharmacol 2014;387:545–557.CrossRefGoogle ScholarPubMed
36. Broekkamp, CL, De Graaf, JS, van Delft, AM. Behavioural pharmacology of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro- 1H-dibenz[2,3:6,7]oxepino-[4,5-c]pyrrolidine maleate, a compound interacting with dopaminergic and serotonergic receptors. Arzneimittelforschung 1990;40:544–549.Google Scholar
37. Ene, HM, Kara, NZ, Einat, H. The effects of the atypical antipsychotic asenapine in a strain-specific battery of tests for mania-like behaviors. Behav Pharmacol 2015;26:331–337.CrossRefGoogle Scholar
38. Thompson, BL, Rosen, JB. Immediate-early gene expression in the central nucleus of the amygdala is not specific for anxiolytic or anxiogenic drugs. Neuropharmacology 2006;50:57–68.CrossRefGoogle ScholarPubMed
39. Wisłowska-Stanek, A, Zienowicz, M, Lehner, M et al. Buspirone attenuates conditioned fear-induced c-Fos expression in the rat hippocampus. Neurosci Lett 2005;389:115–120.CrossRefGoogle ScholarPubMed
40. Kakui, N, Yokoyama, F, Yamauchi, M et al. Anxiolytic-like profile of mirtazapine in rat conditioned fear stress model: Functional significance of 5-hydroxytryptamine 1A receptor and alpha1-adrenergic receptor. Pharmacol Biochem Behav 2009;92:393–398.CrossRefGoogle ScholarPubMed
41. Millan, MJ. Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Therapie 2005;60:441–460.CrossRefGoogle ScholarPubMed
42. Harvey, ML, Swallows, CL, Cooper, MA. A double dissociation in the effects of 5-HT2A and 5-HT2C receptors on the acquisition and expression of conditioned defeat in Syrian hamsters. Behav Neurosci 2012;126:530–537.CrossRefGoogle ScholarPubMed
43. Bagdy, G, Graf, M, Anheuer, ZE, Modos, EA, Kantor, S. 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 2001;4:399–408.CrossRefGoogle Scholar
44. Dekeyne, A, Mannoury la Cour, C, Gobert, A et al. S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models. Psychopharmacology (Berl) 2008;199:549–568.CrossRefGoogle ScholarPubMed
45. Masuda, T, Nishikawa, H, Inoue, T et al. 5-HT depletion, but not 5-HT1A antagonist, prevents the anxiolytic-like effect of citalopram in rat contextual conditioned fear stress model. Acta Neuropsychiatr 2013;25:77–84.CrossRefGoogle ScholarPubMed
46. Martin, JR, Ballard, TM, Higgins, GA. Influence of the 5-HT2C receptor antagonist, SB-242084, in tests of anxiety. Pharmacol Biochem Behav 2002;71:615–625.CrossRefGoogle ScholarPubMed
47. Huang, M, Li, Z, Dai, J, Shahid, M, Wong, EH, Meltzer, HY. Asenapine increases dopamine, norepinephrine, and acetylcholine efflux in the rat medial prefrontal cortex and hippocampus. Neuropsychopharmacology 2008;33:2934–2945.CrossRefGoogle ScholarPubMed
48. Kennett, G, Lightowler, S, Trail, B, Bright, F, Bromidge, S. Effects of RO60 0175, a 5-HT2C receptor agonist, in three animal models of anxiety. Eur J Pharmacol 2000;387:197–204.CrossRefGoogle Scholar
49. Takamura, N, Masuda, T, Inoue, T, Nakagawa, S, Koyama, T. The effects of the co-administration of the α1-adrenoreceptor antagonist prazosin on the anxiolytic effect of citalopram in conditioned fear stress in the rat. Prog Neuropsychopharmacol Biol Psychiatry 2012;39:107–111.CrossRefGoogle ScholarPubMed
50. Frånberg, O, Marcus, MM, Ivanov, V, Schilström, B, Shahid, M, Svensson, TH. Asenapine elevates cortical dopamine, noradrenaline and serotonin release. Evidence for activation of cortical and subcortical dopamine systems by different mechanisms. Psychopharmacology (Berl) 2009;204:254–264.CrossRefGoogle ScholarPubMed
51. Assié, MB, Ravailhe, V, Faucillon, V, Newman-Tancredi, A. Contrasting contribution of 5-hydroxytryptamine 1A receptor activation to neurochemical profile of novel antipsychotics: frontocortical dopamine and hippocampal serotonin release in rat brain. J Pharmacol Exp Ther 2005;315:265–272.CrossRefGoogle ScholarPubMed
52. Hedlund, PB. The 5-HT7 receptor and disorders of the nervous system: an overview. Psychopharmacology (Berl) 2009;206:345–354.CrossRefGoogle ScholarPubMed
53. Wesołowska, A. Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data. Pharmacol Rep 2010;62:564–577.CrossRefGoogle ScholarPubMed