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CGRP in a gene–environment interaction model for depression: effects of antidepressant treatment

Published online by Cambridge University Press:  04 December 2018

Francesco Angelucci ,
Bart A Ellenbroek ,
Aram El Khoury  and
Aleksander A. Mathé
Francesco Angelucci
Affiliation:
Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic
Bart A Ellenbroek*
Affiliation:
Behavioural Neurogenetics Group, School of Psychology, Victoria University of Wellington, New Zealand
Aram El Khoury
Affiliation:
Institution of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, S-171 77Sweden
Aleksander A. Mathé
Affiliation:
Institution of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, S-171 77Sweden
*
Author for correspondence: Bart Ellenbroek, Victoria University Wellington, School of Psychology, Behavioural Neurogenetics Group, Wellington 6041, New Zealand. Tel: +61 4 463 6159; E-mail: bart.ellenbroek@vuw.ac.nz
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Abstract

Objective

Genetic and environmental factors interact in the development of major depressive disorder (MDD). While neurobiological correlates have only partially been elucidated, altered levels of calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) in animal models and in the cerebrospinal fluid of depressed patients were reported, suggesting that CGRP may be involved in the pathophysiology and/or be a trait marker of MDD. However, changes in CGRP brain levels resulting from interactions between genetic and environmental risk factors and the response to antidepressant treatment have not been explored.

Methods

We therefore superimposed maternal separation (MS) onto a genetic rat model (Flinders-sensitive and -resistant lines, FSL/FRL) of depression, treated these rats with antidepressants (escitalopram and nortriptyline) and measured CGRP-LI in selected brain regions.

Results

CGRP was elevated in the frontal cortex, hippocampus and amygdala (but not in the hypothalamus) of FSL rats. However, MS did not significantly alter levels of this peptide. Likewise, there were no significant interactions between the genetic and environmental factors. Most importantly, neither escitalopram nor nortriptyline significantly altered brain CGRP levels.

Conclusion

Our data demonstrate that increased brain levels of CGRP are present in a well-established rat model of depression. Given that antidepressants have virtually no effect on the brain level of this peptide, our study indicates that further research is needed to evaluate the functional role of CGRP in the FSL model for depression.

Keywords

calcitonin gene-related peptideescitalopramFlinders-sensitive linematernal deprivationnortriptyline
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 31 , Issue 2 , April 2019 , pp. 93 - 99
Copyright
© Scandinavian College of Neuropsychopharmacology 2018 

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References

1. DALYs GBD and Collaborators H (2016) Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388, 1603–1658.Google Scholar
2. Iadarola, ND, Niciu, MJ, Richards, EM, Vande Voort, JL, Ballard, ED, Lundin, NB, Nugent, AC, Machado-Vieira, R and Zrata, CA Jr (2015) Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Ther Adv Chronic Dis 6, 97–114.Google Scholar
3. Tundo, A, de Filippis, R and Proietti, L (2015) Pharmacologic approaches to treatment resistant depression: evidences and personal experience. World J Psychiatry 5, 330–341.Google Scholar
4. Sullivan, PF, Neale, MC and Kendler, KS (2000) Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157, 1552–1562.Google Scholar
5. Kendler, KS, Neale, MC, Kessler, RC, Heath, AC and Eaves, LJ (1993) The lifetime history of major depression in women. Reliability of diagnosis and heritability. Arch Gen Psychiatry 50, 863–870.Google Scholar
6. Kendler, KS, Gatz, M, Gardner, CO and Pedersen, NL (2007) Clinical indices of familial depression in the Swedish Twin Registry. Acta Psychiatr Scand 115, 214–220.Google Scholar
7. Ellenbroek, BA and Youn, J (2016) Affective Disorders. Gene–Environment Interactions in psychiatry Nature, nurture, neuroscience. London: Elsevier, 2016.Google Scholar
8. Carola, V, Pascucci, T, Puglisi-Allegra, S, Cabib, S and Gross, C (2011) Effect of the interaction between the serotonin transporter gene and maternal environment on developing mouse brain. Behav Brain Res 217, 188–194.Google Scholar
9. Overstreet, DH and Wegener, G (2013) The flinders sensitive line rat model of depression–25 years and still producing. Pharmacol Rev 65, 143–155.Google Scholar
10. Wegener, G, Mathe, AA and Neumann, ID (2012) Selectively bred rodents as models of depression and anxiety. Curr Top Behav Neurosci 12, 139–187.Google Scholar
11. Friedman, E, Berman, M and Overstreet, D (2006) Swim test immobility in a genetic rat model of depression is modified by maternal environment: a cross-foster study. Develop Psychobiol 48, 169–177.Google Scholar
12. El Khoury, A, Gruber, SHM, Mork, A and Mathe, AA (2006) Adult life behavioral consequences of early maternal separation are alleviated by escitalopram treatment in a rat model of depression. Prog Neuropsychopharmacol Biol Psychiatry 30, 535–540.Google Scholar
13. Ellenbroek, BA, Angelucci, F, Husum, H and Mathe, AA (2016) Gene–environment interactions in a rat model of depression. Maternal separation affects neurotensin in selected brain regions. Neuropeptides 59, 83–88.Google Scholar
14. Wortwein, G, Husum, H, Andersson, W, Bolwig, TG and Mathe, AA (2006) Effects of maternal separation on neuropetide Y and calcitonin gene-related peptide in “depressed” Flinders Sensitive Line rats: A study of gene-environment interactions. Prog Neuropsychopharmacol Biol Psychiatry 30, 684–693.Google Scholar
15. Steenbergh, PH, Hoppener, JW, Zandberg, J, Visser, A, Lips, CJ and Jansz, HS (1986) Structure and expression of the human calcitonin/CGRP genes. FEBS Lett 209, 97–103.Google Scholar
16. Dobolyi, A, Irwin, S, Makara, G, Usdin, TB and Palkovits, M (2005) Calcitonin gene-related peptide-containing pathways in the rat forebrain. J Comp Neurol 489, 92–119.Google Scholar
17. Hay, DL and Walker, CS (2017) CGRP and its receptors. Headache 57, 625–636.Google Scholar
18. Russo, AF (2015) Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol 55, 533–552.Google Scholar
19. van Rossum, D, Hanisch, UK and Quirion, R (1997) Neuroanatomical localization, pharmacological characterization and functions of CGRP-related peptides and their receptors. Neurosci Biobehav Rev 21, 649–678.Google Scholar
20. Mathe, AA, Agren, H, Wallin, A and Blennow, K (2002) Calcitonin gene-related peptide and calcitonin in the CSF of patients with dementia and depression: possible disease markers. Prog Neuropsychopharmacol Biol Psychiatry 26, 41–48.Google Scholar
21. Svenningsson, P, Palhagen, S and Mathe, AA (2017) Neuropeptide Y and calcitonin gene-related peptide in cerebrospinal fluid in Parkinson’s disease with comorbid depression versus patients with major depressive disorder. Front Psychiatry 8, 102.Google Scholar
22. Mathe, AA, Agren, H, Lindstrom, L and Theodorsson, E (1994) Increased concentration of calcitonin gene-related peptide in cerebrospinal fluid of depressed patients. A possible trait marker of major depressive disorder. Neurosci Lett. 182, 138–142.Google Scholar
23. Cizza, G, Marques, AH, Eskandari, F, Christie, IC, Torvik, S and Silverman, MN et al. (2008) Elevated neuroimmune biomarkers in sweat patches and plasma of premenopausal women with major depressive disorder in remission: the POWER study. Biol Psychiatry 64, 907–911.Google Scholar
24. Jiao, J, Opal, MD and Dulawa, SC (2013) Gestational environment programs adult depression-like behavior through methylation of the calcitonin gene-related peptide gene. Mol Psychiatry. 18, 1273–1280.Google Scholar
25. Hashikawa-Hobara, N, Ogawa, T, Sakamoto, Y, Matsuo, Y, Ogawa, M and Zamami, Y et al. (2015) Calcitonin gene-related peptide pre-administration acts as a novel antidepressant in stressed mice. Sci Rep 5, 12559.Google Scholar
26. Husum, H, Wortwein, G, Andersson, W, Bolwig, TG and Mathe, AA (2008) Gene-environment interaction affects substance P and neurokinin A in the entorhinal cortex and periaqueductal grey in a genetic animal model of depression: implications for the pathophysiology of depression. Int J Neuropsychopharmacol 11, 93–101.Google Scholar
27. Husum, H and Mathe, AA (2002) Early life stress changes concentrations of neuropeptide Y and corticotropin-releasing hormone in adult rat brain. Lithium treatment modifies these changes. Neuropsychopharmacology 27, 756–764.Google Scholar
28. Ellenbroek, BA, Angelucci, F, Husum, H and Mathe, AA (2016) Gene-environment interactions in a rat model of depression. Maternal separation affects neurotensin in selected brain regions. Neuropeptides 59, 83–88.Google Scholar
29. Bjornebekk, A, Mathe, AA and Brene, S (2010) The antidepressant effects of running and escitalopram are associated with levels of hippocampal NPY and Y1 receptor but not cell proliferation in a rat model of depression. Hippocampus 20, 820–828.Google Scholar
30. Bjornebekk, A, Mathe, AA, Gruber, SH and Brene, S (2008) Housing conditions modulate escitalopram effects on antidepressive-like behaviour and brain neurochemistry. Int J Neuropsychopharmacol 11, 1135–1147.Google Scholar
31. Hansson, AC, Rimondini, R, Heilig, M, Mathe, AA and Sommer, WH (2011) Dissociation of antidepressant-like activity of escitalopram and nortriptyline on behaviour and hippocampal BDNF expression in female rats. J Psychopharmacol 25, 1378–1387.Google Scholar
32. Piubelli, C, Gruber, S, El Khoury, A, Mathe, AA, Domenici, E and Carboni, L (2011) Nortriptyline influences protein pathways involved in carbohydrate metabolism and actin-related processes in a rat gene-environment model of depression. Europ Neuropsychopharmacol 21, 545–562.Google Scholar
33. Mathe, AA, Stenfors, C, Brodin, E and Theodorsson, E (1990) Neuropeptides in brain: effects of microwave irradiation and decapitation. Life Sci. 46, 287–293.Google Scholar
34. Husum, H, Jimenez-Vasquez, PA and Mathe, AA (2001) Changed concentrations of tachykinins and neuropeptide Y in brain of a ral model of depression: Lithium treatment normalizes tachykinins. Neuropsychopharmacology 24, 183–191.Google Scholar
35. Husum, H, Termeer, E, Mathe, AA, Bolwig, TG and Ellenbroek, BA (2002) Early maternal deprivation alters hippocampal levels of neuropeptide Y and calcitonin-gene related peptide in adult rats. Neuropharmacology 42, 798–806.Google Scholar
36. Mathe, AA, Gruber, S, Jimenez, PA, Theodorsson, E and Stenfors, C (1997) Effects of electroconvulsive stimuli and MK-801 on neuropeptide Y, neurokinin A, and calcitonin gene-related peptide in rat brain. Neurochem Res 22, 629–636.Google Scholar
37. Angelucci, F, Gruber, SH and Mathe, AA (2001) A pilot study of rat brain regional distribution of calcitonin, katacalcin and calcitonin gene-related peptide before and after antipsychotic treatment. Neuropeptides 35, 285–291.Google Scholar
38. Gillman, PK (2007) Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol 151, 737–748.Google Scholar
39. Arvidsson, U, Schalling, M, Cullheim, S, Ulfhake, B, Terenius, L and Verhofstad, A et al. (1990) Evidence for coexistence between calcitonin gene-related peptide and serotonin in the bulbospinal pathway in the monkey. Brain Res 532, 47–57.Google Scholar
40. Fu, W, Le Maitre, E, Fabre, V, Bernard, JF, David Xu, ZQ and Hokfelt, T (2010) Chemical neuroanatomy of the dorsal raphe nucleus and adjacent structures of the mouse brain. The Journal of comparative neurology 518, 3464–3494.Google Scholar
41. Durham, PL and Russo, AF (2002) New insights into the molecular actions of serotonergic antimigraine drugs. Pharmacol Ther 94, 77–92.Google Scholar
42. Greco, MC, Navarra, P and Tringali, G (2016) The analgesic agent tapentadol inhibits calcitonin gene-related peptide release from isolated rat brainstem via a serotonergic mechanism. Life Sci 145, 161–165.Google Scholar
43. Tsuda, K, Tsuda, S, Goldstein, M, Nishio, I and Masuyama, Y (1992) Calcitonin gene-related peptide in noradrenergic transmission in rat hypothalamus. Hypertension 19, 639–642.Google Scholar
44. Mai, TH, Wu, J, Diedrich, A, Garland, EM and Robertson, D (2014) Calcitonin gene-related peptide (CGRP) in autonomic cardiovascular regulation and vascular structure. J Am Soc Hypertens 8, 286–296.Google Scholar
45. Yadid, G, Nakash, R, Deri, I, Tamar, G, Kinor, N and Gispan, I et al. (2000) Elucidation of the neurobiology of depression: insights from a novel genetic animal model. ProgNeurobiol 62, 353–378.Google Scholar
46. Pucilowski, O, Overstreet, DH, Rezvani, AH and Janowsky, DS (1993) Chronic mild stress-induced anhedonia: greater effect in a genetic rat model of depression. Physiol Behav 54, 1215–1220.Google Scholar
47. Bernstein, C and Burstein, R (2012) Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol 8, 89–99.Google Scholar
48. Coyle, CM and Laws, KR (2015) The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharm 30, 152–163.Google Scholar
49. Ryan, B, Musazzi, L, Mallei, A, Tardito, D, Gruber, SH and El Khoury, A et al. (2009) Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression. Int J Neuropsychopharmacol 12, 553–559.Google Scholar
50. Bigio, B, Mathe, AA, Sousa, VC, Zelli, D, Svenningsson, P and McEwen, BS et al. (2016) Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance. Proc Natl Acad Sci U S A 113, 7906–7911.Google Scholar
51. Nasca, C, Xenos, D, Barone, Y, Caruso, A, Scaccianoce, S and Matrisciano, F et al. (2013) L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc Natl Acad Sci U S A 110, 4804–4809.Google Scholar
52. Bigal, ME, Walter, S and Rapoport, AM (2013) Calcitonin gene-related peptide (CGRP) and migraine current understanding and state of development. Headache 53, 1230–1244.Google Scholar
53. Peroutka, SJ (2014) Calcitonin gene-related peptide targeted immunotherapy for migraine: progress and challenges in treating headache. BioDrugs 28, 237–244.Google Scholar