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Exploring a post-traumatic stress disorder paradigm in Flinders sensitive line rats to model treatment-resistant depression I: bio-behavioural validation and response to imipramine

Published online by Cambridge University Press:  30 August 2016

Sarel Jacobus Brand  and
Brian Herbert Harvey
Sarel Jacobus Brand
Affiliation:
Division of Pharmacology, North-West University, Potchefstroom, South Africa
Brian Herbert Harvey*
Affiliation:
Division of Pharmacology, North-West University, Potchefstroom, South Africa Center of Excellence for Pharmaceutical Sciences, MRC Unit on Anxiety and Stress Disorders, North-West University, Potchefstroom, South Africa
*
Brian H. Harvey, Center of Excellence for Pharmaceutical Sciences, MRC Unit on Stress and Anxiety Disorders, North-West University (Potchefstroom Campus), Hoffman Street, Potchefstroom, 2531, South Africa. Tel: +27 18 299-2238; Fax: +27 87 231 5432; E-mail: [email protected]
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Abstract

Objective

Co-morbid depression with post-traumatic stress disorder (PTSD) is often treatment resistant. In developing a preclinical model of treatment-resistant depression (TRD), we combined animal models of depression and PTSD to produce an animal with more severe as well as treatment-resistant depressive-like behaviours.

Methods

Male Flinders sensitive line (FSL) rats, a genetic animal model of depression, were exposed to a stress re-stress model of PTSD [time-dependent sensitisation (TDS)] and compared with stress-naive controls. Seven days after TDS stress, depressive-like and coping behaviours as well as hippocampal and cortical noradrenaline (NA) and 5-hydroxyindoleacetic acid (5HIAA) levels were analysed. Response to sub-chronic imipramine treatment (IMI; 10 mg/kg s.c.×7 days) was subsequently studied.

Results

FSL rats demonstrated bio-behavioural characteristics of depression. Exposure to TDS stress in FSL rats correlated negatively with weight gain, while demonstrating reduced swimming behaviour and increased immobility versus unstressed FSL rats. IMI significantly reversed depressive-like (immobility) behaviour and enhanced active coping behaviour (swimming and climbing) in FSL rats. The latter was significantly attenuated in FSL rats exposed to TDS versus unstressed FSL rats. IMI reversed reduced 5HIAA levels in unstressed FSL rats, whereas exposure to TDS negated this effect. Lowered NA levels in FSL rats were sustained after TDS with IMI significantly reversing this in the hippocampus.

Conclusion

Combining a gene-X-environment model of depression with a PTSD paradigm produces exaggerated depressive-like symptoms that display an attenuated response to antidepressant treatment. This work confirms combining FSL rats with TDS exposure as a putative animal model of TRD.

Keywords

animal modelantidepressantgene-environment modelpost-traumatic stress disordertreatment-resistant depression
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 29 , Issue 4 , August 2017 , pp. 193 - 206
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Copyright
© Scandinavian College of Neuropsychopharmacology 2016 

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References

1. Fava, M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003;53:649–659.CrossRefGoogle ScholarPubMed
2. Trivedi, MH, Rush, AJ, Wisniewski, SR et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006;163:28–40.CrossRefGoogle ScholarPubMed
3. Rush, AJ, Fava, M, Wisniewski, SR et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials 2004;25:119–142.Google Scholar
4. Nierenberg, AA, Amsterdam, JD. Treatment-resistant depression: definition and treatment approaches. J Clin Psychiatry 1990;51(Suppl. 6):39–47.Google Scholar
5. Brand, SJ, Möller, M, Harvey, BH. A review of biomarkers in mood and psychotic disorders: a dissection of clinical vs. preclinical correlates. Curr Neuropharmacol 2015;13:324–368.CrossRefGoogle ScholarPubMed
6. Harvey, BH. Is major depressive disorder a metabolic encephalopathy? Hum Psychopharmacol 2008;23:371–384.CrossRefGoogle ScholarPubMed
7. Krishnan, V, Nestler, EJ. The molecular neurobiology of depression. Nature 2008;455:894–902.Google Scholar
8. Wijeratne, C, Sachdev, P. Treatment-resistant depression: critique of current approaches. Aust N Z J Psychiatry 2008;42:751–762.CrossRefGoogle ScholarPubMed
9. Rush, AJ, Trivedi, MH, Wisniewski, SR et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163:1905–1917.Google Scholar
10. Zarate, CA Jr, Singh, JB, Carlson, PJ et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63:856–864.Google Scholar
11. Ford, JD, Elhai, JD, Ruggiero, KJ, Frueh, BC. Refining posttraumatic stress disorder diagnosis: evaluation of symptom criteria with the national survey of adolescents. J Clin Psychiatry 2009;70:748–755.CrossRefGoogle ScholarPubMed
12. Elhai, JD, De Francisco Carvalho, L, Miguel, FK, Palmieri, PA, Primi, R, Christopher Frueh, B. Testing whether posttraumatic stress disorder and major depressive disorder are similar or unique constructs. J Anxiety Disord 2011;25:404–410.CrossRefGoogle ScholarPubMed
13. Manji, HK, Drevets, WC, Charney, DS. The cellular neurobiology of depression. Nat Med 2001;7:541–547.Google Scholar
14. Tennant, C. Life events, stress and depression: a review of recent findings. Aust N Z J Psychiatry 2002;36:173–182.Google Scholar
15. Caspi, A, Sugden, K, Moffitt, TE et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301:386–389.Google Scholar
16. Sullivan, PF, Neale, MC, Kendler, KS. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000;157:1552–1562.Google Scholar
17. Harvey, BH, Shahid, M. Metabotropic and ionotropic glutamate receptors as neurobiological targets in anxiety and stress-related disorders: focus on pharmacology and preclinical translational models. Pharmacol Biochem Behav 2012;100:775–800.Google Scholar
18. Levinstein, MR, Samuels, BA. Mechanisms underlying the antidepressant response and treatment resistance. Front Behav Neurosci 2014;8:208, (Published online; eCollection 2014).Google Scholar
19. Willner, P, Belzung, C. Treatment-resistant depression: are animal models of depression fit for purpose? Psychopharmacology (Berl) 2015;232:3473–3495.Google Scholar
20. Katz, RJ. Animal model of depression: pharmacological sensitivity of a hedonic deficit. Pharmacol Biochem Behav 1982;16:965–968.Google Scholar
21. Jayatissa, MN, Bisgaard, C, Tingström, A, Papp, M, Wiborg, O. Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacology 2006;31:2395–2404.CrossRefGoogle Scholar
22. Willner, P. Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology (Berl) 1997;134:319–329.Google Scholar
23. Samuels, BA, Leonardo, ED, Gadient, R et al. Modeling treatment-resistant depression. Neuropharmacology 2011;61:408–413.Google Scholar
24. Yadid, G, Nakash, R, Deri, I et al. Elucidation of the neurobiology of depression: insights from a novel genetic animal model. Prog Neurobiol 2000;62:353–378.Google Scholar
25. Abildgaard, A, Solskov, L, Volke, V, Harvey, BH, Lund, S, Wegener, G. A high-fat diet exacerbates depressive-like behavior in the Flinders sensitive line (FSL) rat, a genetic model of depression. Psychoneuroendocrinology 2011;36:623–633.Google Scholar
26. Overstreet, DH. The flinders sensitive line rats: a genetic animal model of depression. Neurosci Biobehav Rev 1993;17:51–68.Google Scholar
27. Overstreet, DH, Wegener, G. The Flinders sensitive line rat model of depression – 25 years and still producing. Pharmacol Rev 2013;65:143–155.Google Scholar
28. Matthews, K, Forbes, N, Reid, IC. Sucrose consumption as an hedonic measure following chronic unpredictable mild stress. Physiol Behav 1995;57:241–248.Google Scholar
29. Pucilowski, O, Overstreet, DH, Rezvani, AH, Janowsky, DS. Chronic mild stress-induced anhedonia: greater effect in a genetic rat model of depression. Physiol Behav 1993;54:1215–1220.Google Scholar
30. Shrestha, SS, Pine, DS, Luckenbaugh, DA et al. Antidepressant effects on serotonin 1A/1B receptors in the rat brain using a gene x environment model. Neurosci Lett 2014;559:163–168.CrossRefGoogle ScholarPubMed
31. Shrestha, S, Hirvonen, J, Hines, CS et al. Serotonin-1A receptors in major depression quantified using PET: controversies, confounds, and recommendations. NeuroImage 2012;59:3243–3251.Google Scholar
32. Ruf, BM, Bhagwagar, Z. The 5-HT1B receptor: a novel target for the pathophysiology of depression. Curr Drug Targets 2009;10:1118–1138.Google Scholar
33. Carboni, L, Becchi, S, Piubelli, C et al. Early-life stress and antidepressants modulate peripheral biomarkers in a gene-environment rat model of depression. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:1037–1048.Google Scholar
34. Green, BL, Krupnick, JL, Chung, J et al. Impact of PTSD comorbidity on one-year outcomes in a depression trial. J Clin Psychol 2006;62:815–835.Google Scholar
35. Thase, ME, Rush, AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997;58(Suppl. 13):23–29.Google ScholarPubMed
36. Oosthuizen, F, Wegener, G, Harvey, BH. Nitric oxide as inflammatory mediator in post-traumatic stress disorder (PTSD): evidence from an animal model. Neuropsychiatr Dis Treat 2005;1:109–123.Google Scholar
37. Harvey, BH, Naciti, C, Brand, L, Stein, DJ. Endocrine, cognitive and hippocampal/cortical 5HT1A/2 A receptor changes evoked by a time-dependent sensitisation (TDS) stress model in rats. Brain Res 2003;983:97–107.CrossRefGoogle Scholar
38. Harvey, BH, Oosthuizen, F, Brand, L, Wegener, G, Stein, DJ. Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology 2004;175:494–502.Google Scholar
39. Harvey, BH, Naciti, C, Brand, L, Stein, DJ. Serotonin and stress: protective or malevolent actions in the biobehavioral response to repeated Trauma? Ann N Y Acad Sci 2004;1032:267–272.Google Scholar
40. Liberzon, I, Krstov, M, Young, EA. Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology 1997;22:443–453.Google Scholar
41. Yehuda, R, Antelman, SM. Criteria for rationally evaluating animal models of postraumatic stress disorder. Biol Psychiatry 1993;33:479–486.Google Scholar
42. Harvey, BH, Brand, L, Jeeva, Z, Stein, DJ. Cortical/hippocampal monoamines, HPA-axis changes and aversive behavior following stress and restress in an animal model of post-traumatic stress disorder. Physiol Behav 2006;87:881–890.Google Scholar
43. Porsolt, RD, Anton, G, Blavet, N, Jalfre, M. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 1978;47:379–391.Google Scholar
44. Harvey, BH, Duvenhage, I, Viljoen, F et al. Role of monoamine oxidase, nitric oxide synthase and regional brain monoamines in the antidepressant-like effects of methylene blue and selected structural analogues. Biochem Pharmacol 2010;80:1580–1591.CrossRefGoogle ScholarPubMed
45. Wróbel, A, Serefko, A, Wlaź, P, Poleszak, E. The depressogenic-like effect of acute and chronic treatment with dexamethasone and its influence on the activity of antidepressant drugs in the forced swim test in adult mice. Prog Neuropsychopharmacol Biol Psychiatry 2014;54:243–248.Google Scholar
46. Wainwright, SR, Workman, JL, Tehrani, A et al. Testosterone has antidepressant-like efficacy and facilitates imipramine-induced neuroplasticity in male rats exposed to chronic unpredictable stress. Horm Behav 2016;79:58–69.Google Scholar
47. Breuer, ME, Groenink, L, Oosting, RS, Westenberg, HGM, Olivier, B. Long-term behavioral changes after cessation of chronic antidepressant treatment in olfactory bulbectomized rats. Biol Psychiatry 2007;61:990–995.CrossRefGoogle ScholarPubMed
48. Breuer, ME, Chan, JSW, Oosting, RS et al. The triple monoaminergic reuptake inhibitor DOV 216,303 has antidepressant effects in the rat olfactory bulbectomy model and lacks sexual side effects. Eur Neuropsychopharmacol 2008;18:908–916.Google Scholar
49. Shannon, NJ, Gunnet, JW, Moore, KE. A comparison of biochemical indices of 5-hydroxytryptaminergic neuronal activity following electrical stimulation of the dorsal raphe nucleus. J Neurochem 1986;47:958–965.CrossRefGoogle ScholarPubMed
50. Duncan, JS. Neurotransmitters, drugs and brain function. Br J Clin Pharmacol 2002;53:648.Google Scholar
51. Mehlman, PT, Westergaard, GC, Hoos, BJ et al. CSF 5-HIAA and nighttime activity in free-ranging primates. Neuropsychopharmacology 2000;22:210–218.Google Scholar
52. Harris, RBS, Zhou, J, Youngblood, BD, Rybkin, II, Smagin, GN, Ryan, DH. Effect of repeated stress on body weight and body composition of rats fed low- and high-fat diets. Am J Physiol 1998;275:R1928–R1938.Google Scholar
53. Harris, RBS, Palmondon, J, Leshin, S, Flatt, WP, Richard, D. Chronic disruption of body weight but not of stress peptides or receptors in rats exposed to repeated restraint stress. Horm Behav 2006;49:615–625.Google Scholar
54. Espejo, EF, Miñano, FJ. Prefrontocortical dopamine depletion induces antidepressant-like effects in rats and alters the profile of desipramine during Porsolt’s test. Neuroscience 1999;88:609–615.Google Scholar
55. Hayes, DJ, Greenshaw, AJ. 5-HT receptors and reward-related behaviour: a review. Neurosci Biobehav Rev 2011;35:1419–1449.Google Scholar
56. Andrews, PW, Bharwani, A, Lee, KR, Fox, M, Thomson, JA. Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response. Neurosci Biobehav Rev 2015;51:164–188.Google Scholar
57. Deakin, JFW. Roles of serotonergic systems in escape, avoidance and other behaviours In: Cooper S, editor. Theories in Psychopharmacology, Academic Press, London/New York, 1983;179–204.Google Scholar
58. Daw, ND, Kakade, S, Dayan, P. Opponent interactions between serotonin and dopamine. Neural Netw 2002;15:603–616.Google Scholar
59. Kirby, LG, Allen, AR, Lucki, I. Regional differences in the effects of forced swimming on extracellular levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. Brain Res 1995;682:189–196.Google Scholar
60. Zangen, A, Overstreet, DH, Yadid, G. High serotonin and 5-hydroxyindoleacetic acid levels in limbic brain regions in a rat model of depression: normalization by chronic antidepressant treatment. J Neurochem 1997;69:2477–2483.Google Scholar
61. Ahmad, A, Rasheed, N, Banu, N, Palit, G. Alterations in monoamine levels and oxidative systems in frontal cortex, striatum, and hippocampus of the rat brain during chronic unpredictable stress. Stress 2010;13:355–364.Google Scholar
62. Detke, MJ, Rickels, M, Lucki, I. Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology 1995;121:66–72.Google Scholar
63. Cottingham, C, Wang, Q. α2 adrenergic receptor dysregulation in depressive disorders: Implications for the neurobiology of depression and antidepressant therapy. Neurosci Biobehav Rev 2012;36:2214–2225.Google Scholar
64. Maes, M, Lin, A-H, Verkerk, R et al. Serotonergic and noradrenergic markers of post-traumatic stress disorder with and without major depression. Neuropsychopharmacology 1999;20:188–197.Google Scholar
65. Schosser, A, Calati, R, Serretti, A et al. The impact of COMT gene polymorphisms on suicidality in treatment resistant major depressive disorder – A European Multicenter Study. Eur Neuropsychopharmacol 2012;22:259–266.Google Scholar
66. Yamada, S, Yamauchi, K, Yajima, J et al. Saliva level of free 3-methoxy-4-hydroxyphenylglycol (MHPG) as a biological index of anxiety disorders. Psychiatry Res 2000;93:217–223.Google Scholar
67. Leonard, BE. Noradrenaline in basic models of depression. Eur Neuropsychopharmacol 1997;7(Suppl. 1):S11–S16.Google Scholar
68. Weiss, JM, Goodman, PA, Losito, BG, Corrigan, S, Charry, JM, Bailey, WH. Behavioral depression produced by an uncontrollable stressor: relationship to norepinephrine, dopamine, and serotonin levels in various regions of rat brain. Brain Res Rev 1981;3:167–205.Google Scholar
69. Dimsdale, JE, Mills, P, Patterson, T, Ziegler, M, Dillon, E. Effects of chronic stress on beta-adrenergic receptors in the homeless. Psychosom Med 1994;56:290–295.Google Scholar
70. Flügge, G. Alterations in the central nervous α2-adrenoceptor system under chronic psychosocial stress. Neuroscience 1996;75:187–196.Google Scholar
71. Tejani-Butt, SM, Paré, WP, Yang, J. Effect of repeated novel stressors on depressive behavior and brain norepinephrine receptor system in Sprague-Dawley and Wistar Kyoto (WKY) rats. Brain Res 1994;649:27–35.Google Scholar
72. Richelson, E. Pharmacology of antidepressants. Mayo Clin Proc 2001;76:511–527.Google Scholar
73. Willner, P, Scheel-Krüger, J, Belzung, C. The neurobiology of depression and antidepressant action. Neurosci Biobehav Rev 2013;37:2331–2371.Google Scholar
74. Surget, A, Wang, Y, Leman, S et al. Corticolimbic transcriptome changes are state-dependent and region-specific in a rodent model of depression and of antidepressant reversal. Neuropsychopharmacology 2009;34:1363–1380.Google Scholar
75. Brand, SJ, Harvey, BH. Exploring a post-traumatic stress disorder paradigm in Flinders sensitive line rats to model treatment resistant depression II: Response to antidepressant augmentation strategies. Acta Neuropsychiatrica (in press).Google Scholar