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Depressive-like neurochemical and behavioral markers of Parkinson’s disease after 6-OHDA administered unilaterally to the rat medial forebrain bundle

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Abstract

Background

Although Parkinson’s disease (PD) is characterized by progressive neurodegeneration of multiple neurotransmitter systems, 6-hydroxydopamine (6-OHDA) as a model substance is mainly used to selectively damage the nigrostriatal dopaminergic neurons and induce parkinsonian-like motor disturbances in rats. We hypothesized that high doses of this neurotoxin affecting other monoaminergic systems may also evoke the depressive-like behavior.

Methods

The impact of 6-OHDA (8, 12, 16 μg/4 μl) administered unilaterally into the medial forebrain bundle on the sucrose solution intake (a measure of anhedonia) and on the tissue levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the striatum (STR), substantia nigra (SN), prefrontal cortex (PFC) and hippocampus (HIP) was examined in rats pretreated or non-pretreated with desipramine.

Results

The highest dose of 6-OHDA reduced the preference for 3% sucrose solution both in rats without and with desipramine pretreatment. All used doses of 6-OHDA dramatically decreased DA content in the studied brain structures on the ipsilateral side. NA levels were severely decreased in the ipsilateral STR, HIP and PFC of rats non-pretreated with desipramine and to a much lesser extent in those pretreated with desipramine. In the SN, moderate decreases in NA level were found both in rats pretreated and non-pretreated with desipramine. Higher doses of 6-OHDA reduced 5-HT content in the ipsilateral STR, HIP and PFC, but not in the SN, only in rats non-pretreated with desipramine.

Conclusions

Administration of the highest dose of 6-OHDA without desipramine pretreatment evoked neurochemical and behavioral changes resembling the advanced PD with coexisting depression.

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Abbreviations

APO:

apomorphine

DA:

dopamine

HIP:

hippocampus

5-HT:

serotonin

LC:

locus coeruleus

MFB:

medial forebrain bundle

NA:

noradrenaline

6-OHDA:

6-hydroxydopamine

PD:

Parkinson’s disease

PFC:

prefrontal cortex

SN:

substantia nigra

STR:

striatum

References

  1. Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79(4):368–76.

    Article  CAS  PubMed  Google Scholar 

  2. Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol 2009;8(5):464–74.

    Article  CAS  PubMed  Google Scholar 

  3. Simuni T, Sethi K. Nonmotor manifestations of Parkinson’s disease. Ann Neurol 2008;64(Suppl 2):S65–80.

    PubMed  Google Scholar 

  4. McDonald WM, Richard IH, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinson’s disease. Biol Psychiatry 2003;54(3):363–75.

    Article  PubMed  Google Scholar 

  5. Chan-Palay V, Asan E. Alterations in catecholamine neurons of the locus coeruleus in senile dementia of the Alzheimer type and in Parkinson’s disease with and without dementia and depression. J Comp Neurol 1989;287(3):373–92.

    Article  CAS  PubMed  Google Scholar 

  6. Halliday GM, Blumbergs PC, Cotton RG, Blessing WW, Geffen LB. Loss of brainstem serotonin- and substance P-containing neurons in Parkinson’s disease. Brain Res 1990;510(1):104–7.

    Article  CAS  PubMed  Google Scholar 

  7. Paulus W, Jellinger K. The neuropathologic basis of different clinical subgroups of Parkinson’s disease. J Neuropathol Exp Neurol 1991;50(6):743–55.

    Article  CAS  PubMed  Google Scholar 

  8. Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004;318(1):121–34.

    Article  PubMed  Google Scholar 

  9. Heinz A, Schmidt LG, Reischies FM. Anhedonia in schizophrenic, depressed, or alcohol-dependent patients-neurobiological correlates. Pharmacopsychiatry 1994;27(Suppl. 1):7–10.

    Article  PubMed  Google Scholar 

  10. Remy P, Doder M, Lees A, Turjanski N, Brooks D. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 2005;128:1314–22.

    Article  PubMed  Google Scholar 

  11. Kish SJ, Tong J, Hornykiewicz O, Rajput A, Chang LJ, Guttman M, et al. Preferential loss of serotonin markers in caudate versus putamen in Parkinson’s disease. Brain 2008;131(Pt 1):120–31.

    PubMed  Google Scholar 

  12. Shannak K, Rajput A, Rozdilsky B, Kish S, Gilbert J, Hornykiewicz O. Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson’s disease and normal subjects. Brain Res 1994;639(1):33–41.

    Article  CAS  PubMed  Google Scholar 

  13. D’Amato RJ, Zweig RM, Whitehouse PJ, Wenk GL, Singer HS, Mayeux R, et al. Aminergic systems in Alzheimer’s disease and Parkinson’s disease. Ann Neurol 1987;22(2):229–36.

    Article  PubMed  Google Scholar 

  14. Scatton B, Javoy-Agid F, Rouquier L, Dubois B, Agid Y. Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson’s disease. Brain Res 1983;275(2):321–8.

    Article  CAS  PubMed  Google Scholar 

  15. Winter C, von Rumohr A, Mundt A, Petrus D, Klein J, Lee T, et al. Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats. Behav Brain Res 2007;184(2):133–41.

    Article  CAS  PubMed  Google Scholar 

  16. Branchi I, D’Andrea I, Armida M, Cassano T, Pèzzola A, Potenza RL, et al. Nonmotor symptoms in Parkinson’s disease: investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model. J Neurosci Res 2008;86(9):2050–61.

    Article  CAS  PubMed  Google Scholar 

  17. Tadaiesky MT, Dombrowski PA, Figueiredo CP, Cargnin-Ferreira E, Da Cunha C, Takahashi RN. Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson’s disease. Neuroscience 2008; 156(4):830–40.

    Article  CAS  PubMed  Google Scholar 

  18. Ossowska K, Lorenc-Koci E. Depression in Parkinson’s disease. Pharmacol Rep 2013;65(6):1545–57.

    Article  CAS  PubMed  Google Scholar 

  19. Santiago RM, Barbiero J, Gradowski RW, Bochen S, Lima MM, Da Cunha C, et al. Induction of depressive-like behavior by intranigral 6-OHDA is directly correlated with deficits in striatal dopamine and hippocampal serotonin. Behav Brain Res 2014;259:70–7.

    Article  CAS  PubMed  Google Scholar 

  20. Schwarting RK, Huston JP. The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Prog Neurobiol 1996;50(2–3):275–331.

    CAS  PubMed  Google Scholar 

  21. Kelly PH. Iversen SD: selective 6-OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats. Eur J Pharmacol 1976;40(1):45–56.

    Article  CAS  PubMed  Google Scholar 

  22. Lorenc-Koci E, Czarnecka A, Lenda T, Kamińska K, Molsidomine Konieczny J. a nitric oxide donor, modulates rotational behavior and monoamine metabolism in 6-OHDA lesioned rats treated chronically with L-DOPA. Neurochem Int 2013;63(8):790–804.

    Article  CAS  PubMed  Google Scholar 

  23. Czarnecka A, Lenda T, Domin H, Konieczny J. Śmialowska M, Lorenc-Koci E Alterations in the expression of nNOS in the substantia nigra and subthalamic nucleus of 6-OHDA-lesioned rats: the effects of chronic treatment with 1-DOPA and the nitric oxide donor, molsidomine. Brain Res 2013;1541:92–105.

    Article  CAS  PubMed  Google Scholar 

  24. Papp M, Willner P, Muscat R. An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psychopharmacology (Berl) 1991;104(2):255–9.

    Article  CAS  Google Scholar 

  25. Slattery DA, Markou A, Cryan JF. Evaluation of reward processes in an animal model of depression. Psychopharmacology (Berl) 2007;190(4):555–68.

    Article  CAS  Google Scholar 

  26. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. San Diego: Academic Press; 1986.

    Google Scholar 

  27. Frau L, Morelli M, Simola N. Performance of movement in hemiparkinsonian rats influences the modifications induced by dopamine agonists in striatal efferent dynorphinergic neurons. Exp Neurol 2013;247:663–72.

    Article  CAS  PubMed  Google Scholar 

  28. Deumens R, Blokland A, Prickaerts J. Modeling Parkinson’s disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol 2002;175(2):303–17.

    Article  CAS  PubMed  Google Scholar 

  29. Imai H. Steindler DA, Kitai ST: the organization of divergent axonal projections from the midbrain raphe nuclei in the rat. J Comp Neurol. 1986;243(3):363–80.

    Article  CAS  PubMed  Google Scholar 

  30. Blier P. El Mansari M: The importance of serotonin and noradrenaline in anxiety. Int J Psychiatry Clin Pract 2007;11(Suppl. 2):16–23.

    Article  CAS  PubMed  Google Scholar 

  31. Karstaedt PJ, Kerasidis H, Pincus JH, Meloni R, Graham J, Gale K. Unilateral destruction of dopamine pathways increases ipsilateral striatal serotonin turnover in rats. Exp Neurol 1994;126(1):25–30.

    Article  CAS  PubMed  Google Scholar 

  32. Hyttel J. Pharmacological characterization of selective serotonin reuptake inhibitors (SSRIs). Int Clin Psychopharmacol 1994;9(Suppl 1):19–26.

    Article  PubMed  Google Scholar 

  33. Kannari K, Shen H, Arai A, Tomiyama M, Baba M Kannari K, Shen H, Arai A, Tomiyama M, Baba M. Reuptake of L-DOPA-derived extracellular dopamine in the striatum with dopaminergic denervation via serotonin transporters. Neurosci Lett 2006;402(1–2):62–5.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland

    Kinga Kamińska, Tomasz Lenda, Jolanta Konieczny, Anna Czarnecka & Elżbieta Lorenc-Koci

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  1. Kinga Kamińska
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  2. Tomasz Lenda
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  3. Jolanta Konieczny
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  5. Elżbieta Lorenc-Koci
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Correspondence to Elżbieta Lorenc-Koci.

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Kamińska, K., Lenda, T., Konieczny, J. et al. Depressive-like neurochemical and behavioral markers of Parkinson’s disease after 6-OHDA administered unilaterally to the rat medial forebrain bundle. Pharmacol. Rep 69, 985–994 (2017). https://doi.org/10.1016/j.pharep.2017.05.016

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  • DOI: https://doi.org/10.1016/j.pharep.2017.05.016

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