Skip to main content Accessibility help
×
Home

Long-term effects of pre-pubertal fluoxetine on behaviour and monoaminergic stress response in stress-sensitive rats

  • Nico Johan Badenhorst (a1), Linda Brand (a1), Brian Herbert Harvey (a1) (a2), Susanna Maria Ellis (a3) and Christiaan Beyers Brink (a1)...

Abstract

Objective

Although prescription rates of antidepressants for children and adolescents have increased, concerns have been raised regarding effects on neurodevelopment and long-term outcome. Using a genetic animal model of depression, this study investigated the long-term effects of pre-pubertal administration of fluoxetine (FLX) on depressive-like behaviour in early adulthood, as well as on central monoaminergic response to an acute stressor. We postulated that pre-pubertal FLX will have lasting effects on animal behaviour and monoaminergic stress responses in early adulthood.

Methods

Flinders sensitive line (FSL) rats received 10 mg/kg/day FLX subcutaneously from postnatal day 21 (PnD21) to PnD34 (pre-pubertal). Thereafter, following normal housing, rats were either subjected to locomotor testing and the forced swim test (FST) on PnD60 (early adulthood), or underwent surgery for microdialysis, followed on PnD60 by exposure to acute swim stress and measurement of stressor-induced changes in plasma corticosterone and pre-frontal cortical monoamine concentrations.

Results

Pre-pubertal FLX did not induce a late emergent effect on immobility in FSL rats on PnD60, whereas locomotor activity was significantly decreased. Acute swim stress on PnD60 significantly increased plasma corticosterone levels, and increased pre-frontal cortical norepinephrine (NE) and 5-hydroxyindole-3-acetic acid (5-HIAA) concentrations. Pre-pubertal FLX significantly blunted the pre-frontal cortical NE and 5-HIAA response following swim stress on PnD60. Baseline dopamine levels were significantly enhanced by pre-pubertal FLX, but no further changes were induced by swim stress.

Conclusion

Pre-pubertal FLX did not have lasting antidepressant-like behavioural effects in genetically susceptible, stress-sensitive FSL rats. However, such treatment reduced locomotor activity, abrogated noradrenergic and serotonergic stressor responses and elevated dopaminergic baseline levels in adulthood.

Copyright

Corresponding author

Christiaan B. Brink, Pharmacology, School of Pharmacy, North-West University (PUK), Internal box 16, Potchefstroom, 2520, South Africa. Tel: +27 0 18 299 2234; Fax: +27 18 299 2225; E-mail: Tiaan.Brink@nwu.ac.za

References

Hide All
1. Marcus, M, Yasamy, MT, van Ommeren, M, Chisholm, D, Saxena, S. Depression: a global public health concern. WHO Department of Mental Health and Substance Abuse. No. 1; 2012, p. 6–8. Available at http://www.who.int/mental_health/management/depression/who_paper_depression_wfmh_2012.pdf
2. Birmaher, B, Ryan, ND, Williamson, DE et al. Childhood and adolescent depression: a review of the past 10 years. Part I. J Am Acad Child Adolesc Psychiatry 1996;35:14271439.
3. Costello, JE, Erkanli, A, Angold, A. Is there an epidemic of child or adolescent depression? J Child Psychol Psychiatry 2006;47:12631271.
4. Kessler, RC, Birnbaum, H, Bromet, E, Hwang, I, Sampson, N, Shahly, V. Age differences in major depression: results from the National Comorbidity Survey Replication (NCS-R). Psychol Med 2010;40:225237.
5. Rohde, P, Lewinsohn, PM, Klein, DN, Seeley, JR, Gau, JM. Key characteristics of major depressive disorder occurring in childhood, adolescence, emerging adulthood, adulthood. Clin Psychol Sci 2013;1:121.
6. Egger, HL, Angold, A. Common emotional and behavioral disorders in preschool children: presentation, nosology, and epidemiology. J Child Psychol Psychiatry 2006;47:313337.
7. Thapar, A, Collishaw, S, Pine, DS, Thapar, AK. Depression in adolescence. Lancet 2012;379:10561067.
8. Zito, JM, Safer, DJ, DosReis, S et al. Psychotropic practice patterns for youth: a 10-year perspective. Arch Pediatr Adolesc Med 2003;157:1725.
9. Baxter, AJ, Scott, KM, Ferrari, AJ, Norman, RE, Vos, T, Whiteford, HA. Challenging the myth of an “epidemic” of common mental disorders: trends in the global prevalence of anxiety and depression between 1990 and 2010. Depress Anxiety 2014;31:506516.
10. Soutullo, C, Figueroa-Quintana, A. When do you prescribe antidepressants to depressed children? Curr Psychiatry Rep 2013;15:366.
11. Cabrera-Vera, TM, Garcia, F, Pinto, W, Battaglia, G. Effect of prenatal fluoxetine (Prozac) exposure on brain serotonin neurons in prepubescent and adult male rat offspring. J Pharmacol Exp Ther 1997;280:138145.
12. Hansen, HH, Mikkelsen, JD. Long-term effects on serotonin transporter mRNA expression of chronic neonatal exposure to a serotonin reuptake inhibitor. Eur J Pharmacol 1998;352:307315.
13. Manhaes de Castro, R, Barreto Medeiros, JM, Mendes da Silva, C et al. Reduction of intraspecific aggression in adult rats by neonatal treatment with a selective serotonin reuptake inhibitor. Braz J Med Biol Res 2001;34:121124.
14. Mulder, EJ, Ververs, FF, de Heus, R, Visser, GH. Selective serotonin reuptake inhibitors affect neurobehavioral development in the human fetus. Neuropsychopharmacology 2011;36:19611971.
15. Ansorge, MS, Morelli, E, Gingrich, JA. Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice. J Neurosci 2008;28:199207.
16. Kepser, LJ, Homberg, JR. The neurodevelopmental effects of serotonin: a behavioural perspective. Behav Brain Res 2015;277:313.
17. Soga, T, Wong, DW, Putteeraj, M, Song, KP, Parhar, IS. Early-life citalopram-induced impairments in sexual behavior and the role of androgen receptor. Neuroscience 2012;225:172184.
18. Rodriguez-Porcel, F, Green, D, Khatri, N et al. Neonatal exposure of rats to antidepressants affects behavioral reactions to novelty and social interactions in a manner analogous to autistic spectrum disorders. Anat Rec 2011;294:17261735.
19. Freund, N, Thompson, BS, Denormandie, J, Vaccarro, K, Andersen, SL. Windows of vulnerability: maternal separation, age, and fluoxetine on adolescent depressive-like behavior in rats. Neuroscience 2013;249:8897.
20. McNamara, IM, Borella, AW, Bialowas, LA, Whitaker-Azmitia, PM. Further studies in the developmental hyperserotonemia model (DHS) of autism: social, behavioral and peptide changes. Brain Res 2008;1189:203214.
21. O’Donnell, JM, Shelton, RC. Drug therapy of depression and anxiety disorders, 12th edn. New York: McGraw-Hill, 2011; p. 397415.
22. Gaspar, P, Cases, O, Maroteaux, L. The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 2003;4:10021012.
23. Rayen, I, van den Hove, DL, Prickaerts, J, Steinbusch, HW, Pawluski, JL. Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence. PLoS One 2011;6:e24003.
24. Ehlert, U, Gaab, J, Heinrichs, M. Psychoneuroendocrinological contributions to the etiology of depression, posttraumatic stress disorder, and stress-related bodily disorders: the role of the hypothalamus-pituitary-adrenal axis. Biol Psychol 2001;57:141152.
25. Kvetnansky, R, Sabban, EL, Palkovits, M. Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiol Rev 2009;89:535606.
26. Leonard, BE. The immune system, depression and the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 2001;25:767780.
27. Rueter, LE, Fornal, CA, Jacobs, BL. A critical review of 5-HT brain microdialysis and behavior. Rev Neurosci 1997;8:117137.
28. Schiepers, OJ, Wichers, MC, Maes, M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:201217.
29. Brand, SJ, Moller, M, Harvey, BH. A review of biomarkers in mood and psychotic disorders: a dissection of clinical vs. preclinical correlates. Curr Neuropharmacol 2015;13:324368.
30. Lesch, KP, Waider, J. Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. Neuron 2012;76:175191.
31. Roy, V, Merali, Z, Poulter, MO, Anisman, H. Anxiety responses, plasma corticosterone and central monoamine variations elicited by stressors in reactive and nonreactive mice and their reciprocal F1 hybrids. Behav Brain Res 2007;185:4958.
32. Overstreet, DH, Wegener, G. The Flinders sensitive line rat model of depression—25 years and still producing. Pharmacol Rev 2013;65:143155.
33. Bjornebekk, A, Mathe, AA, Brene, S. Isolated Flinders sensitive line rats have decreased dopamine D2 receptor mRNA. Neuroreport 2007;18:10391043.
34. Shayit, M, Yadid, G, Overstreet, DH, Weller, A. 5-HT(1A) receptor subsensitivity in infancy and supersensitivity in adulthood in an animal model of depression. Brain Res 2003;980:100108.
35. Gomez, ML, Martinez-Mota, L, Estrada-Camarena, E, Fernandez-Guasti, A. Influence of the brain sexual differentiation process on despair and antidepressant-like effect of fluoxetine in the rat forced swim test. Neuroscience 2014;261:1122.
36. Hansen, F, de Oliveira, DL, Amaral, FU et al. Effects of chronic administration of tryptophan with or without concomitant fluoxetine in depression-related and anxiety-like behaviors on adult rat. Neurosci Lett 2011;499:5963.
37. First, M, Gil-Ad, I, Taler, M, Tarasenko, I, Novak, N, Weizman, A. The effects of fluoxetine treatment in a chronic mild stress rat model on depression-related behavior, brain neurotrophins and ERK expression. J Mol Neurosci 2011;45:246255.
38. Liebenberg, N, Harvey, BH, Brand, L, Brink, CB. Antidepressant-like properties of phosphodiesterase type 5 inhibitors and cholinergic dependency in a genetic rat model of depression. Behav Pharmacol 2010;21:540547.
39. Overstreet, DH, Griebel, G. Antidepressant-like effects of CRF1 receptor antagonist SSR125543 in an animal model of depression. Eur J Pharmacol 2004;497:4953.
40. Saenz del Burgo, L, Cortes, R, Mengod, G, Montana, M, Garcia del Cano, G, Salles, J. Chronic effects of corticosterone on GIRK1-3 subunits and 5-HT1A receptor expression in rat brain and their reversal by concurrent fluoxetine treatment. Eur Neuropsychopharmacol 2013;23:229239.
41. Murrin, LC, Sanders, JD, Bylund, DB. Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: implications for differential drug effects on juveniles and adults. Biochem Pharmacol 2007;73:12251236.
42. Kalsbeek, A, Voorn, P, Buijs, RM, Pool, CW, Uylings, HB. Development of the dopaminergic innervation in the prefrontal cortex of the rat. J Comp Neurol 1988;269:5872.
43. Karanges, E, McGregor, IS. Antidepressants and adolescent brain development. Future Neurol 2011;6:783808.
44. Kotronoulas, A, Pizarro, N, Serra, A et al. Dose-dependent metabolic disposition of hydroxytyrosol and formation of mercapturates in rats. Pharmacol Res 2013;77:4756.
45. Visser, GP. Cortical brain release of glutamate by ketamine and fluoxetine: an in vivo microdialysis study in the Flinders sensitive line rat. Dissertation. Potchefstroom: North-West University, 2012.
46. Porsolt, RD, Le Pichon, M, Jalfre, M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977;266:730732.
47. Lucki, I. The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav Pharmacol 1997;8:523532.
48. Cryan, JF, Markou, A, Lucki, I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 2002;23:238245.
49. Castagne, V, Moser, P, Roux, S, Porsolt, RD. Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Curr Protoc Neurosci 2011; 55:8.10A:8.10A.1–8.10A.14.
50. Golembiowska, K, Kowalska, M, Bymaster, FP. Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity. Synapse 2012;66:435444.
51. Kirby, LG, Chou-Green, JM, Davis, K, Lucki, I. The effects of different stressors on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. Brain Res 1997;760:218230.
52. Purdy, RH, Morrow, AL, Moore, PH Jr, Paul, SM. Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci U S A 1991;88:45534557.
53. Schwartz, RD, Wess, MJ, Labarca, R, Skolnick, P, Paul, SM. Acute stress enhances the activity of the GABA receptor-gated chloride ion channel in brain. Brain Res 1987;411:151155.
54. Paxinos, G, Watson, C. The Rat Brain in Stereotaxic Coordinates, 6th edn. London: Elsevier Academic Press, 2005.
55. Wegener, G, Volke, V, Rosenberg, R. Endogenous nitric oxide decreases hippocampal levels of serotonin and dopamine in vivo. Br J Pharmacol 2000;130:575580.
56. 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;87:881890.
57. Bert, L, Favale, D, Jego, G et al. Rapid and precise method to locate microdialysis probe implantation in the rodent brain. J Neurosci Methods 2004;140:5357.
58. IHC-World. Nissl staining method and protocol on frozen or vibratome sections for brain & spinal cord, 2011. Available at http://www.ihcworld.com/_protocols/special_stains/nissl-frozen-section.htm.
59. Viljoen, FP, Brand, L, Smit, EJ. An optimized method for the analysis of corticosterone in rat plasma by UV-HPLC. Med Technol SA 2012;26:3942.
60. Marais, L, Daniels, W, Brand, L, Viljoen, F, Hugo, C, Stein, DJ. Psychopharmacology of maternal separation anxiety in vervet monkeys. Metab Brain Dis 2006;21:191200.
61. Kobayashi, K, Ikeda, Y, Asada, M, Inagaki, H, Kawada, T, Suzuki, H. Corticosterone facilitates fluoxetine-induced neuronal plasticity in the hippocampus. PloS One 2013;8:e63662.
62. Gualda, LB, Martins, GG, Muller, B, Guimaraes, FS, Oliveira, RM. 5-HT1A autoreceptor modulation of locomotor activity induced by nitric oxide in the rat dorsal raphe nucleus. Braz J Med Biol Res 2011;44:332336.
63. Mignon, L, Wolf, WA. Postsynaptic 5-HT(1A) receptors mediate an increase in locomotor activity in the monoamine-depleted rat. Psychopharmacology (Berl) 2002;163:8594.
64. Halberstadt, AL, van der Heijden, I, Ruderman, MA et al. 5-HT(2A) and 5-HT(2C) receptors exert opposing effects on locomotor activity in mice. Neuropsychopharmacology 2009;34:19581967.
65. McOmish, CE, Lira, A, Hanks, JB, Gingrich, JA. Clozapine-induced locomotor suppression is mediated by 5-HT2A receptors in the forebrain. Neuropsychopharmacology 2012;37:27472755.
66. Martin, JR, Bos, M, Jenck, F et al. 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther 1998;286:913924.
67. Neumann, ID, Wegener, G, Homberg, JR et al. Animal models of depression and anxiety: what do they tell us about human condition? Prog Neuropsychopharmacol Biol Psychiatry 2011;35:13571375.
68. Overstreet, DH, Friedman, E, Mathe, AA, Yadid, G. The Flinders sensitive line rat: a selectively bred putative animal model of depression. Neurosci Biobehav Rev 2005;29:739759.
69. Mokoena, ML, Harvey, BH, Viljoen, F, Ellis, SM, Brink, CB. Ozone exposure of Flinders sensitive line rats is a rodent translational model of neurobiological oxidative stress with relevance for depression and antidepressant response. Psychopharmacology (Berl) 2015;232:29212938.
70. 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;47:958965.
71. Zangen, A, Nakash, R, Overstreet, DH, Yadid, G. Association between depressive behavior and absence of serotonin-dopamine interaction in the nucleus accumbens. Psychopharmacology (Berl) 2001;155:434439.
72. Dremencov, E, Newman, ME, Kinor, N et al. Hyperfunctionality of serotonin-2C receptor-mediated inhibition of accumbal dopamine release in an animal model of depression is reversed by antidepressant treatment. Neuropharmacology 2005;48:3442.
73. Dremencov, E, Gispan-Herman, I, Rosenstein, M et al. The serotonin-dopamine interaction is critical for fast-onset action of antidepressant treatment: in vivo studies in an animal model of depression. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:141147.
74. Yadid, G, Overstreet, DH, Zangen, A. Limbic dopaminergic adaptation to a stressful stimulus in a rat model of depression. Brain Res 2001;896:4347.
75. Pizzagalli, DA. Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu Rev Clin Psychol 2014;10:393423.
76. Lunardi, G, Galati, S, Tropepi, D et al. Correlation between changes in CSF dopamine turnover and development of dyskinesia in Parkinson’s disease. Parkinsonism Relat Disord 2009;15:383389.
77. Vidal, L, Alfonso, M, Campos, F, Faro, LRF, Cervantes, RC, Duran, R. Effects of manganese on extracellular levels of dopamine in rat striatum: an analysis in vivo by brain microdialysis. Neurochem Res 2005;30:11471154.
78. Fagergren, P, Overstreet, DH, Goiny, M, Hurd, YL. Blunted response to cocaine in the Flinders hypercholinergic animal model of depression. Neuroscience 2005;132:11591171.
79. Torres, GE, Gainetdinov, RR, Caron, MG. Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 2003;4:1325.
80. Amphoux, A, Vialou, V, Drescher, E et al. Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology 2006;50:941952.
81. Wu, X, Kekuda, R, Huang, W et al. Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 1998;273:3277632786.
82. Gasser, PJ, Lowry, CA, Orchinik, M. Corticosterone-sensitive monoamine transport in the rat dorsomedial hypothalamus: potential role for organic cation transporter 3 in stress-induced modulation of monoaminergic neurotransmission. J Neurosci 2006;26:87588766.
83. Gasser, PJ, Orchinik, M, Raju, I, Lowry, CA. Distribution of organic cation transporter 3, a corticosterone-sensitive monoamine transporter, in the rat brain. J Comp Neurol 2009;512:529555.
84. Taubert, D, Grimberg, G, Stenzel, W, Schömig, E. Identification of the endogenous key substrates of the human organic cation transporter OCT2 and their implication in function of dopaminergic neurons. PLoS One 2007;2:e385.

Keywords

Related content

Powered by UNSILO

Long-term effects of pre-pubertal fluoxetine on behaviour and monoaminergic stress response in stress-sensitive rats

  • Nico Johan Badenhorst (a1), Linda Brand (a1), Brian Herbert Harvey (a1) (a2), Susanna Maria Ellis (a3) and Christiaan Beyers Brink (a1)...

Metrics

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.