Hostname: page-component-cd9895bd7-jkksz Total loading time: 0 Render date: 2024-12-19T01:04:25.790Z Has data issue: false hasContentIssue false
  • English
  • Français

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

Published online by Cambridge University Press:  26 June 2015

Amanda Juliana Sales  and
Sâmia Regiane Lourenço Joca
Amanda Juliana Sales
Affiliation:
Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto-SP, Brazil
Sâmia Regiane Lourenço Joca*
Affiliation:
Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto-SP, Brazil Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Ribeirão Preto-SP, Brazil
*
Sâmia Joca, FCFRP-USP, Av Café, sn, Monte Alegre, Ribeirão Preto-SP 14040-903, Brazil. Tel: +55 163 315 4705; Fax: +55 163 315 4880; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective

Stress increases DNA methylation and decreases the expression of genes involved in neural plasticity, while treatment with DNA methyltransferase inhibitors (DNMTi) increases gene expression and induces antidepressant-like effects in preclinical models. Therefore, the aim of the present work was to further investigate the potential antidepressant-like effect induced by DNMTi by evaluating the behavioural effects induced by associating DNMTi treatment with conventional antidepressant drugs in mice submitted to the forced swimming test (FST). In addition, brain levels of DNA methylation were also investigated.

Methods

Mice received systemic injections of 5-aza-2'-deoxycytidine (5-AzaD, 0.1, 0.2 mg/kg), RG108 (0.1, 0.2, 0.4 mg/kg), desipramine (DES, 2.5, 5, 10 mg/kg) or fluoxetine (FLX, 5, 10, 20, 30 mg/kg) and were submitted to the FST or to the open field test (OFT). Additional groups received a combination of subeffective doses of 5-AzaD or RG108 (DNMTi) with subeffective doses of DES or FLX (antidepressants).

Results

Subeffective doses of RG108 (0.1 mg/kg) or 5-AzaD (0.1mg/kg) in association with subeffective doses of DES (2.5 mg/kg) or FLX (10 mg/kg) induced significant antidepressant-like effects. Effective doses of RG108 (0.2 mg/kg), 5-AzaD (0.2 mg/kg), DES (10 mg/kg) and FLX (20 mg/kg) atenuated stress-induced changes in DNA methylation levels in the hippocampus and prefrontal cortex. None of the treatments induced locomotor effects in the OFT.

Conclusion

These results suggest that DNMTi potentiate the behavioural effects of antidepressant drugs in the FST and that antidepressants, as well as DNMTi, are able to modulate stress-induced changes in DNA methylation in brain regions closely associated with the neurobiology of depression.

Keywords

AntidepressantDNA methylationRG1085-AzaD
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 28 , Issue 1 , February 2016 , pp. 11 - 22
Check for updates
Copyright
© Scandinavian College of Neuropsychopharmacology 2015 

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. Kessler, RC, Berglund, P, Demler, O et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289:3095–3105.Google Scholar
2. Kessler, R, White, LA, Birnbaum, H et al. Comparative and interactive effects of depression relative to other health problems on work performance in the workforce of a large employer. J Occup Environ Med 2008;50:809–816.CrossRefGoogle ScholarPubMed
3. Rosenzweig-Lipson, S, Beyer, CE, Hughes, ZA et al. Differentiating antidepressants of the future: efficacy and safety. Pharmacol Ther 2007;113:134–153.Google Scholar
4. Castren, E. Is mood chemistry? Nat Rev Neurosci 2005;6:241–246.Google Scholar
5. Krishnan, V, Nestler, EJ. The molecular neurobiology of depression. Nature 2008;455:894–902.Google Scholar
6. Racagni, G, Popoli, M. Cellular and molecular mechanisms in the long-term action of antidepressants. Dialogues Clin Neurosci 2008;10:385–400.Google Scholar
7. Schmidt, HD, Shelton, RC, Duman, RS. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 2011;36:2375–2394.Google Scholar
8. Archer, T, Oscar-Berman, M, Blum, K, Gold, M. Neurogenetics and epigenetics in impulsive behaviour: impact on reward circuitry. J Genet Syndr Gene Ther 2012;3:1000115.CrossRefGoogle ScholarPubMed
9. Saveanu, RV, Nemeroff, CB. Etiology of depression: genetic and environmental factors. Psychiatr Clin North Am 2012;35:51–71.Google Scholar
10. Castren, E, Rantamaki, T. The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 2010;70:289–297.Google Scholar
11. Kimpton, J. The brain derived neurotrophic factor and influences of stress in depression. Psychiatr Danub 2012;24(Suppl 1):S169–S171.Google ScholarPubMed
12. Checkley, S. Monoamines, depression and antidepressant drugs. Pharmacopsychiatry 1988;21:6–8.Google Scholar
13. Klengel, T, Pape, J, Binder, EB, Mehta, D. The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology 2014;80:115–132.Google Scholar
14. Urdinguio, RG, Sanchez-Mut, JV, Esteller, M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol 2009;8:1056–1072.CrossRefGoogle ScholarPubMed
15. Iraola-Guzman, S, Estivill, X, Rabionet, R. DNA methylation in neurodegenerative disorders: a missing link between genome and environment? Clin Genet 2011;80:1–14.Google Scholar
16. Qureshi, IA, Mehler, MF. Epigenetic mechanisms underlying human epileptic disorders and the process of epileptogenesis. Neurobiol Dis 2010;39:53–60.Google Scholar
17. Maric, NP, Svrakic, DM. Why schizophrenia genetics needs epigenetics: a review. Psychiatr Danub 2012;24:2–18.Google Scholar
18. Nguyen, S, Meletis, K, Fu, D, Jhaveri, S, Jaenisch, R. Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan. Dev Dyn 2007;236:1663–1676.Google Scholar
19. Miller, CA, Sweatt, JD. Covalent modification of DNA regulates memory formation. Neuron 2007;53:857–869.CrossRefGoogle ScholarPubMed
20. Miller, CA, Campbell, SL, Sweatt, JD. DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity. Neurobiol Learn Mem 2008;89:599–603.Google Scholar
21. Weber, M, Hellmann, I, Stadler, MB et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 2007;39:457–466.Google Scholar
22. Vialou, V, Feng, J, Robison, AJ, Nestler, EJ. Epigenetic mechanisms of depression and antidepressant action. Annu Rev Pharmacol Toxicol 2013;53:59–87.Google Scholar
23. Higuchi, F, Uchida, S, Yamagata, H et al. State-dependent changes in the expression of DNA methyltransferases in mood disorder patients. J Psychiatr Res 2011;45:1295–1300.Google Scholar
24. McGowan, PO, Sasaki, A, Huang, TC et al. Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS One 2008;3:e2085.CrossRefGoogle ScholarPubMed
25. Poulter, MO, Du, L, Weaver, IC et al. GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes. Biol Psychiatry 2008;64:645–652.CrossRefGoogle ScholarPubMed
26. Uchida, S, Hara, K, Kobayashi, A et al. Epigenetic status of Gdnf in the ventral striatum determines susceptibility and adaptation to daily stressful events. Neuron 2011;69:359–372.CrossRefGoogle ScholarPubMed
27. Keller, S, Sarchiapone, M, Zarrilli, F et al. Increased BDNF promoter methylation in the Wernicke area of suicide subjects. Arch Gen Psychiatry 2010;67:258–267.Google Scholar
28. Kang, HJ, Kim, JM, Lee, JY et al. BDNF promoter methylation and suicidal behavior in depressive patients. J Affect Disord 2013;151:679–685.Google Scholar
29. Sales, AJ, Biojone, C, Terceti, MS, Guimaraes, FS, Gomes, MV, Joca, SR. Antidepressant-like effect induced by systemic and intra-hippocampal administration of DNA methylation inhibitors. Br J Pharmacol 2011;164:1711–1721.CrossRefGoogle ScholarPubMed
30. Zimmermann, N, Zschocke, J, Perisic, T, Yu, S, Holsboer, F, Rein, T. Antidepressants inhibit DNA methyltransferase 1 through reducing G9a levels. Biochem J 2012;448:93–102.Google Scholar
31. Porsolt, RD, Bertin, A, Jalfre, M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977;229:327–336.Google Scholar
32. O’Leary, OF, Zandy, S, Dinan, TG, Cryan, JF. Lithium augmentation of the effects of desipramine in a mouse model of treatment-resistant depression: a role for hippocampal cell proliferation. Neuroscience 2013;228:36–46.Google Scholar
33. Mendez, P, Pazienti, A, Szabo, G, Bacci, A. Direct alteration of a specific inhibitory circuit of the hippocampus by antidepressants. J Neurosci 2012;32:16616–16628.CrossRefGoogle ScholarPubMed
34. Abel, EL, Bilitzke, PJ. A possible alarm substance in the forced swimming test. Physiol Behav 1990;48:233–239.Google Scholar
35. Zanelati, TV, Biojone, C, Moreira, FA, Guimaraes, FS, Joca, SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 2010;159:122–128.Google Scholar
36. Schildkraut, JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 1965;122:509–522.Google Scholar
37. Schildkraut, JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. 1965. J Neuropsychiatry Clin Neurosci 1995;7:524–533. discussion 3–4.Google Scholar
38. Blier, P, de Montigny, C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci 1994;15:220–226.Google Scholar
39. Anacker, C, Zunszain, PA, Carvalho, LA, Pariante, CM. The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 2011;36:415–425.Google Scholar
40. Ampuero, E, Rubio, FJ, Falcon, R et al. Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex. Neuroscience 2010;169:98–108.Google Scholar
41. Agid, Y, Buzsaki, G, Diamond, DM et al. How can drug discovery for psychiatric disorders be improved? Nat Rev Drug Discov 2007;6:189–201.Google Scholar
42. Gundersen, BB, Briand, LA, Onksen, JL, Lelay, J, Kaestner, KH, Blendy, JA. Increased hippocampal neurogenesis and accelerated response to antidepressants in mice with specific deletion of CREB in the hippocampus: role of cAMP response-element modulator tau. J Neurosci 2013;33:13673–13685.CrossRefGoogle ScholarPubMed
43. Rantamaki, T, Hendolin, P, Kankaanpaa, A et al. Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain. Neuropsychopharmacology 2007;32:2152–2162.Google Scholar
44. Hisaoka, K, Maeda, N, Tsuchioka, M, Takebayashi, M. Antidepressants induce acute CREB phosphorylation and CRE-mediated gene expression in glial cells: a possible contribution to GDNF production. Brain Res 2008;1196:53–58.Google Scholar
45. Saarelainen, T, Hendolin, P, Lucas, G et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 2003;23:349–357.CrossRefGoogle ScholarPubMed
46. Koponen, E, Rantamaki, T, Voikar, V, Saarelainen, T, MacDonald, E, Castren, E. Enhanced BDNF signaling is associated with an antidepressant-like behavioral response and changes in brain monoamines. Cell Mol Neurobiol 2005;25:973–980.CrossRefGoogle ScholarPubMed
47. Sun, H, Kennedy, PJ, Nestler, EJ. Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology 2013;38:124–137.CrossRefGoogle ScholarPubMed
48. Borrelli, E, Nestler, EJ, Allis, CD, Sassone-Corsi, P. Decoding the epigenetic language of neuronal plasticity. Neuron 2008;60:961–974.CrossRefGoogle ScholarPubMed
49. Mazzio, EA, Soliman, KF. Basic concepts of epigenetics: impact of environmental signals on gene expression. Epigenetics 2012;7:119–130.Google Scholar
50. Grayson, DR, Guidotti, A. The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmacology 2013;38:138–166.Google Scholar
51. LaPlant, Q, Vialou, V, Covington, HE 3rd et al. Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci 2010;13:1137–1143.CrossRefGoogle ScholarPubMed
52. Melas, PA, Rogdaki, M, Lennartsson, A et al. Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression. Int J Neuropsychopharmacol 2012;15:669–679.Google Scholar
53. Levenson, JM, Roth, TL, Lubin, FD et al. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 2006;281:15763–15773.Google Scholar
54. Willner, P, Scheel-Kruger, J, Belzung, C. The neurobiology of depression and antidepressant action. Neurosci Biobehav Rev 2013;37(10 Pt 1):2331–2371.Google Scholar
55. Roth, TL, Zoladz, PR, Sweatt, JD, Diamond, DM. Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. J Psychiatr Res 2011;45:919–926.Google Scholar
56. Popoli, M, Yan, Z, McEwen, BS, Sanacora, G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 2012;13:22–37.Google Scholar
57. Chandramohan, Y, Droste, SK, Arthur, JS, Reul, JM. The forced swimming-induced behavioural immobility response involves histone H3 phospho-acetylation and c-Fos induction in dentate gyrus granule neurons via activation of the N-methyl-D-aspartate/extracellular signal-regulated kinase/mitogen- and stress-activated kinase signalling pathway. Eur J Neurosci 2008;27:2701–2713.Google Scholar
58. Karsten, CA, Baram, TZ. How does a neuron “know” to modulate its epigenetic machinery in response to early-life environment/experience? Front Psychiatry 2013;4:89.CrossRefGoogle ScholarPubMed
59. Ma, DK, Jang, MH, Guo, JU et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 2009;323:1074–1077.Google Scholar
60. Guo, JU, Ma, DK, Mo, H et al. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat Neurosci 2011;14:1345–1351.Google Scholar
61. Wu, H, Zhang, Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 2014;156:45–68.Google Scholar
62. Sui, L, Wang, Y, Ju, LH, Chen, M. Epigenetic regulation of reelin and brain-derived neurotrophic factor genes in long-term potentiation in rat medial prefrontal cortex. Neurobiol Learn Mem 2012;97:425–440.CrossRefGoogle ScholarPubMed