Abstract
Depression is a highly prevalent and debilitating non-motor symptom observed during the early stages of Parkinson’s disease (PD). Although PD prevalence is higher in men, the depressive symptoms in PD are more common in women. Therefore, the aim of this study was to investigate the development of anhedonic- and depressive-like behaviors in male and female mice and the potential mechanisms related to depressive symptoms in an experimental model of PD. Young adult male and female C57BL/6 mice (3 months old) received a single intranasal (i.n.) administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and were submitted to a battery of behavioral tasks (sucrose consumption, splash test, tail suspension, forced swimming and open field tests) to assess their emotional and motor profiles. Considering the role of sexual hormones in emotional behaviors, the same protocol of i.n. MPTP administration and the splash, tail suspension, and open field tests were conducted in ovariectomized (OVX) and aged C57BL/6 female (20 months old) mice. We also investigated the immunocontent of neurotrophins (BDNF, GDNF, and VEGF) in the hippocampus and prefrontal cortex by western blot. I.n. MPTP administration induced more pronounced anhedonic- and selective depressive-like behaviors in female adult mice, also observed in OVX and aged female mice, with the absence of motor impairments. Furthermore, MPTP induced a more pronounced depletion of neurotrophins in the prefrontal cortex and hippocampus in female than male mice. This study provides new evidence of increased susceptibility of female mice to anhedonic- and depressive-like behaviors following i.n. MPTP administration. The observed gender-related effects of MPTP on emotional parameters seem to be linked to increased depletion of neurotrophins (particularly BDNF and GDNF) in the hippocampus and prefrontal cortex of female mice.
Similar content being viewed by others
References
Aarsland D, Påhlhagen S, Ballard CG, Ehrt U, Svenningsson P (2012) Depression in Parkinson disease—epidemiology, mechanisms and management. Nat Rev Neurol 8:35–47. https://doi.org/10.1038/nrneurol.2011.189
Aguiar AS, Tristão FSM, Amar M, Chevarin C, Lanfumey L, Mongeau R, Corti O, Prediger RD, Raisman-Vozari R (2013) Parkin-knockout mice did not display increased vulnerability to intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neurotox Res 24:280–287. https://doi.org/10.1007/s12640-013-9389-0
Antzoulatos E, Jakowec MW, Petzinger GM, Wood RI (2010) Sex differences in motor behavior in the MPTP mouse model of Parkinson’s disease. Pharmacol Biochem Behav 95:466–472. https://doi.org/10.1016/j.pbb.2010.03.009
Boulle F, van den Hove DL, Jakob SB et al (2012) Epigenetic regulation of the BDNF gene: implications for psychiatric disorders. Mol Psychiatry 17:584–596. https://doi.org/10.1038/mp.2011.107
Boulle F, Massart R, Stragier E, Païzanis E, Zaidan L, Marday S, Gabriel C, Mocaer E, Mongeau R, Lanfumey L (2014) Hippocampal and behavioral dysfunctions in a mouse model of environmental stress: normalization by agomelatine. Transl Psychiatry 4:e485. https://doi.org/10.1038/tp.2014.125
Byers SL, Wiles MV, Dunn SL, Taft RA (2012) Mouse estrous cycle identification tool and images. PLoS One 7:e35538. https://doi.org/10.1371/journal.pone.0035538
Carpentieri A, Díaz De Barboza G, Areco V et al (2012) New perspectives in melatonin uses. Pharmacol Res 65:437–444. https://doi.org/10.1016/j.phrs.2012.01.003
Castro AA, Ghisoni K, Latini A, Quevedo J, Tasca CI, Prediger RDS (2012) Lithium and valproate prevent olfactory discrimination and short-term memory impairments in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rat model of Parkinson’s disease. Behav Brain Res 229:208–215. https://doi.org/10.1016/j.bbr.2012.01.016
Castro AA, Wiemes BP, Matheus FC, Lapa FR, Viola GG, Santos AR, Tasca CI, Prediger RD (2013) Atorvastatin improves cognitive, emotional and motor impairments induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats, an experimental model of Parkinson’s disease. Brain Res 1513:103–116. https://doi.org/10.1016/j.brainres.2013.03.029
Clark-Raymond A, Halaris A (2013) VEGF and depression: a comprehensive assessment of clinical data. J Psychiatr Res 47:1080–1087. https://doi.org/10.1016/j.jpsychires.2013.04.008
d’Anglemont de Tassigny X, Pascual A, López-Barneo J (2015) GDNF-based therapies, GDNF-producing interneurons, and trophic support of the dopaminergic nigrostriatal pathway. Implications for Parkinson’s disease. Front Neuroanat 9:10. https://doi.org/10.3389/fnana.2015.00010
de Kloet ER, Molendijk ML (2016) Coping with the forced swim stressor: towards understanding an adaptive mechanism. Neural Plast 2016:1–13. https://doi.org/10.1155/2016/6503162
Devall AJ, Liu ZW, Lovick TA (2009) Hyperalgesia in the setting of anxiety: sex differences and effects of the oestrous cycle in Wistar rats. Psychoneuroendocrinology 34:587–596. https://doi.org/10.1016/j.psyneuen.2008.10.021
Devall AJ, Santos JM, Lovick TA (2011) Estrous cycle stage influences on neuronal responsiveness to repeated anxiogenic stress in female rats. Behav Brain Res 225:334–340. https://doi.org/10.1016/j.bbr.2011.07.038
Diaz AP, Freitas FC, de Oliveira Thais ME, da Silva Areas FZ, Schwarzbold ML, Debona R, Nunes JC, Guarnieri R, Martinez-Ramirez D, Prediger RD, Wagle Shukla A, Linhares MN, Walz R (2016) Variables associated with physical health-related quality of life in Parkinson’s disease patients presenting for deep brain stimulation. Neurol Sci 37:1831–1837. https://doi.org/10.1007/s10072-016-2681-z
Domellöf ME, Lundin K-F, Edström M, Forsgren L (2017) Olfactory dysfunction and dementia in newly diagnosed patients with Parkinson’s disease. Parkinsonism Relat Disord 38:41–47. https://doi.org/10.1016/j.parkreldis.2017.02.017
Doty RL (2008) The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol. 63(1):7–15. https://doi.org/10.1002/ana.21327
Dubois B, Pillon B (1997) Cognitive deficits in Parkinson’s disease. J Neurol 244:2–8
Duman RS, Li N, Liu RJ, Duric V, Aghajanian G (2012) Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 62:35–41. https://doi.org/10.1016/j.neuropharm.2011.08.044
Elbaz A, Bower JH, Maraganore DM, McDonnell SK, Peterson BJ, Ahlskog JE, Schaid DJ, Rocca WA (2002) Risk tables for parkinsonism and Parkinson’s disease. J Clin Epidemiol 55:25–31
Eskelund A, Budac DP, Sanchez C, Elfving B, Wegener G (2016) Female flinders sensitive line rats show estrous cycle-independent depression-like behavior and altered tryptophan metabolism. Neuroscience 329:337–348. https://doi.org/10.1016/j.neuroscience.2016.05.024
Felicio LS, Nelson JF, Finch CE (1984) Longitudinal studies of estrous cyclicity in aging C57BL/6J mice: II. Cessation of cyclicity and the duration of persistent vaginal cornification. Biol Reprod 31:446–453
Freyaldenhoven TE, Ali SF(1997) Role of heat shock proteins in MPTP-induced neurotoxicity. Ann N Y Acad Sci. 15(825):167–78
Georgiev D, Hamberg K, Hariz M, Forsgren L, Hariz GM (2017) Gender differences in Parkinson’s disease: a clinical perspective. Acta Neurol Scand 136:1–15. https://doi.org/10.1111/ane.12796
Goetz CG, Stebbins GT, Wolff D, DeLeeuw W, Bronte-Stewart H, Elble R, Hallett M, Nutt J, Ramig L, Sanger T, Wu AD, Kraus PH, Blasucci LM, Shamim EA, Sethi KD, Spielman J, Kubota K, Grove AS, Dishman E, Taylor CB (2009) Testing objective measures of motor impairment in early Parkinson’s disease: feasibility study of an at-home testing device. Mov Disord 24:551–556. https://doi.org/10.1002/mds.22379
Greene J, Banasr M, Lee B, Warner-Schmidt J, Duman RS (2009) Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment: pharmacological and cellular characterization. Neuropsychopharmacology 34:2459–2468. https://doi.org/10.1038/npp.2009.68
Hagan JJ, Middlemiss DN, Sharpe PC, Poste GH (1997) Parkinson’s disease: prospects for improved drug therapy. Trends Pharmacol Sci 18:156–163
Hong M, Mukhida K, Mendez I (2008) GDNF therapy for Parkinson’s disease. Expert Rev Neurother 8:1125–1139. https://doi.org/10.1586/14737175.8.7.1125
Howells DW, Porritt MJ, Wong JYF, Batchelor PE, Kalnins R, Hughes AJ, Donnan GA (2000) Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp Neurol 166:127–135. https://doi.org/10.1006/exnr.2000.7483
Idris AI (2012) Ovariectomy/orchidectomy in rodents. Methods Mol Biol (816)545–551. https://doi.org/10.1007/978-1-61779-415-5_34
Itano Y, Kitamura Y, Nomura Y (1995) Biphasic effects of MPP+, a possible parkinsonism inducer, on dopamine content and tyrosine hydroxylase mRNA expression in PC12 cells. Neurochem Int 26:165–171
Kalaria RN, Mitchell MJ, Harik SI (1987) Correlation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity with blood-brain barrier monoamine oxidase activity. Proc Natl Acad Sci U S A 84:3521–3525
Klemann CJHM, Martens GJM, Sharma M, Martens MB, Isacson O, Gasser T, Visser JE, Poelmans G (2017) Integrated molecular landscape of Parkinson’s disease. NPJ Parkinsons Dis 3:14. https://doi.org/10.1038/s41531-017-0015-3
Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902. https://doi.org/10.1038/nature07455
Kumari R, Kumar JBS, Luthra PM (2015) Post-lesion administration of 7-NI attenuated motor and non-motor deficits in 6-OHDA induced bilaterally lesioned female rat model of Parkinson’s disease. Neurosci Lett 589:191–195. https://doi.org/10.1016/j.neulet.2014.12.030
Martynhak BJ, Correia D, Morais LH, Araujo P, Andersen ML, Lima MMS, Louzada FM, Andreatini R (2011) Neonatal exposure to constant light prevents anhedonia-like behavior induced by constant light exposure in adulthood. Behav Brain Res 222:10–14. https://doi.org/10.1016/j.bbr.2011.03.022
Massano J (2011) Parkinson’s disease: a clinical update. Acta Médica Port 24(Suppl 4):827–834
Matheus FC, Aguiar AS, Castro AA et al (2012) Neuroprotective effects of agmatine in mice infused with a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behav Brain Res 235:263–272. https://doi.org/10.1016/j.bbr.2012.08.017
Menza M, Dobkin RD, Marin H, Bienfait K (2010) Sleep disturbances in Parkinson’s disease. Mov Disord 25(Suppl 1):S117–SS22. https://doi.org/10.1002/mds.22788
Miller IN, Cronin-Golomb A (2010) Gender differences in Parkinson’s disease: clinical characteristics and cognition. Mov Disord 25:2695–2703. https://doi.org/10.1002/mds.23388
Moreira ELG, Rial D, Aguiar AS, Figueiredo CP, Siqueira JM, DalBó S, Horst H, de Oliveira J, Mancini G, dos Santos TS, Villarinho JG, Pinheiro FV, Marino-Neto J, Ferreira J, de Bem AF, Latini A, Pizzolatti MG, Ribeiro-do-Valle RM, Prediger RDS (2010) Proanthocyanidin-rich fraction from Croton celtidifolius Baill confers neuroprotection in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine rat model of Parkinson’s disease. J Neural Transm 117:1337–1351. https://doi.org/10.1007/s00702-010-0464-x
Moretti M, Colla A, de Oliveira Balen G, dos Santos DB, Budni J, de Freitas AE, Farina M, Severo Rodrigues AL (2012) Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress. J Psychiatr Res 46:331–340. https://doi.org/10.1016/j.jpsychires.2011.11.009
Moretti M, Neis VB, Matheus FC, Cunha MP, Rosa PB, Ribeiro CM, Rodrigues ALS, Prediger RD (2015) Effects of agmatine on depressive-like behavior induced by intracerebroventricular administration of 1-methyl-4-phenylpyridinium (MPP+). Neurotox Res 28:222–231. https://doi.org/10.1007/s12640-015-9540-1
Nilsson FM, Kessing LV, Sørensen TM et al (2002) Major depressive disorder in Parkinson’s disease: a register-based study. Acta Psychiatr Scand 106:202–211
Obeso JA, Rodriguez-Oroz MC, Rodriguez M, Macias R, Alvarez L, Guridi J, Vitek J, DeLong M (2000) Pathophysiologic basis of surgery for Parkinson’s disease. Neurology 55:S7–S12
Ookubo M, Yokoyama H, Kato H, Araki T (2009) Gender differences on MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in C57BL/6 mice. Mol Cell Endocrinol 311:62–68. https://doi.org/10.1016/j.mce.2009.07.011
Otsuki K, Uchida S, Watanuki T, Wakabayashi Y, Fujimoto M, Matsubara T, Funato H, Watanabe Y (2008) Altered expression of neurotrophic factors in patients with major depression. J Psychiatr Res 42:1145–1153. https://doi.org/10.1016/j.jpsychires.2008.01.010
Patel NK, Gill SS (2007) GDNF delivery for Parkinson’s disease. Acta Neurochir Suppl 97:135–154
Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732
Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 47:379–391. https://doi.org/10.1016/0014-2999(78)90118-8
Prediger RDS (2010) Effects of caffeine in Parkinson’s disease: from neuroprotection to the management of motor and non-motor symptoms. J Alzheimers Dis 20(Suppl 1):S205–S220. https://doi.org/10.3233/JAD-2010-091459
Prediger RD, Aguiar AS Jr, Rojas-Mayorquin AE et al (2010) Single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57BL/6 mice models early preclinical phase of Parkinson's disease. Neurotox Res. 17(2):114–29. https://doi.org/10.1007/s12640-009-9087-0
Prediger RDS, Aguiar ASJ, Moreira ELG et al (2011) The intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a new rodent model to test palliative and neuroprotective agents for Parkinson’s disease. Curr Pharm Des 17:489–507. https://doi.org/10.2174/138161211795164095
Prediger RDS, Aguiar AS, Matheus FC, Walz R, Antoury L, Raisman-Vozari R, Doty RL (2012a) Intranasal administration of neurotoxicants in animals: support for the olfactory vector hypothesis of Parkinson’s disease. Neurotox Res 21:90–116. https://doi.org/10.1007/s12640-011-9281-8
Prediger RDS, Matheus FC, Schwarzbold ML, Lima MMS, Vital MABF (2012b) Anxiety in Parkinson’s disease: a critical review of experimental and clinical studies. Neuropharmacology 62:115–124. https://doi.org/10.1016/j.neuropharm.2011.08.039
Reijnders JSAM, Ehrt U, Weber WEJ, Aarsland D, Leentjens AFG (2008) A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord 23:183–189. https://doi.org/10.1002/mds.21803 quiz 313
Ricci V, Pomponi M, Martinotti G, Bentivoglio A, Loria G, Bernardini S, Caltagirone C, Bria P, Angelucci F (2010) Antidepressant treatment restores brain-derived neurotrophic factor serum levels and ameliorates motor function in Parkinson disease patients. J Clin Psychopharmacol 30:751–753. https://doi.org/10.1097/JCP.0b013e3181fc2ec7
Riedel O, Heuser I, Klotsche J, Dodel R, Wittchen HU, GEPAD Study Group (2010a) Occurrence risk and structure of depression in Parkinson disease with and without dementia: results from the GEPAD study. J Geriatr Psychiatry Neurol 23:27–34. https://doi.org/10.1177/0891988709351833
Riedel O, Klotsche J, Spottke A, Deuschl G, Förstl H, Henn F, Heuser I, Oertel W, Reichmann H, Riederer P, Trenkwalder C, Dodel R, Wittchen HU (2010b) Frequency of dementia, depression, and other neuropsychiatric symptoms in 1,449 outpatients with Parkinson’s disease. J Neurol 257:1073–1082. https://doi.org/10.1007/s00415-010-5465-z
Sampaio TB, Roversi K, Schamne MG, et al (2017) Clinical pharmacology and translational medicine review article the relevance of intranasal route in Parkinson’s disease: from physiopathological alterations to administration of neurotoxins. 1:20–37
Santiago RM, Barbieiro J, Lima MMS, Dombrowski PA, Andreatini R, Vital MABF (2010) Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA, LPS and rotenone models of Parkinson’s disease are predominantly associated with serotonin and dopamine. Prog Neuro-Psychopharmacol Biol Psychiatry 34:1104–1114. https://doi.org/10.1016/j.pnpbp.2010.06.004
Schintu N, Zhang X, Svenningsson P (2012) Studies of depression-related states in animal models of parkinsonism. J Parkinsons Dis 2:87–106. https://doi.org/10.3233/JPD-2012-12076
Schrag A (2004) Psychiatric aspects of Parkinson’s disease—an update. J Neurol 251:795–804. https://doi.org/10.1007/s00415-004-0483-3
Segi-Nishida E, Warner-Schmidt JL, Duman RS (2008) Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus. Proc Natl Acad Sci U S A 105:11352–11357. https://doi.org/10.1073/pnas.0710858105
Sharma AN, da Costa e Silva BFB, Soares JC, Soares JC, Carvalho AF, Quevedo J (2016) Role of trophic factors GDNF, IGF-1 and VEGF in major depressive disorder: a comprehensive review of human studies. J Affect Disord 197:9–20. https://doi.org/10.1016/j.jad.2016.02.067
Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370
Szczepanik JC, de Oliveira PA, de Oliveira J, Mack JM, Engel DF, Rial D, Moreira ELG, de Bem AF, Prediger RD (2016) Caffeine mitigates the locomotor hyperactivity in middle-aged low-density lipoprotein receptor (LDLr)-knockout mice. CNS Neurosci Ther 22:420–422. https://doi.org/10.1111/cns.12544
Tadaiesky MT, Dombrowski PA, Figueiredo CP, Cargnin-Ferreira E, da Cunha C, Takahashi RN (2008) Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson’s disease. Neuroscience 156:830–840. https://doi.org/10.1016/j.neuroscience.2008.08.035
Tolosa E, Compta Y, Gaig C (2007) The premotor phase of Parkinson’s disease. Parkinsonism Relat Disord 13(Suppl):S2–S7. https://doi.org/10.1016/j.parkreldis.2007.06.007
Unzeta M, Baron S, Perez V, Ambrosio S, Mahy N (1994) Sex-related effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine treatment may be related to differences in monoamine oxidase B. Neurosci Lett 176:235–238. https://doi.org/10.1016/0304-3940(94)90090-6
Willner P (2005) Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52:90–110. https://doi.org/10.1159/000087097
Yoon JE, Kim JS, Jang W, Park J, Oh E, Youn J, Park S, Cho JW (2017) Gender differences of nonmotor symptoms affecting quality of life in Parkinson disease. Neurodegener Dis 17:276–280. https://doi.org/10.1159/000479111
Funding
This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Universal 408676/2016-7), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Programa de Apoio aos Núcleos de Excelência (PRONEX - Project NENASC), Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC), FINEP (Financiadora de Estudos e Projetos – IBN-Net no. 01.06.0842-00), and INCT (Instituto Nacional de Ciência e Tecnologia) for Excitotoxicity and Neuroprotection. MGS and JMM receive scholarships from CNPq; MM receives scholarship from CAPES. RW and RDP are supported by research fellowships from CNPq.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
This study was developed in accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institute of Health and was approved by the Committee on Ethics of Animal Experiments of the Universidade Federal de Santa Catarina (protocol number 2895030817). All the efforts were made to minimize the number of animals used and their suffering.
Conflict of Interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Schamne, M.G., Mack, J.M., Moretti, M. et al. The Gender-Biased Effects of Intranasal MPTP Administration on Anhedonic- and Depressive-Like Behaviors in C57BL/6 Mice: the Role of Neurotrophic Factors. Neurotox Res 34, 808–819 (2018). https://doi.org/10.1007/s12640-018-9912-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-018-9912-4