Cellular and Molecular Neurobiology

, Volume 27, Issue 8, pp 985–996 | Cite as

Long-Term L-DOPA Treatment Causes Indiscriminate Increase in Dopamine Levels at the Cost of Serotonin Synthesis in Discrete Brain Regions of Rats

  • Anupom Borah
  • Kochupurackal P. Mohanakumar
Original Paper


(1) The treatment of choice for Parkinson’s disease (PD) is 3,4-dihydroxyphenylalanine (L-DOPA) with peripheral decarboxylase inhibitor, but long-term therapy leads to motor and psychiatric complications. In the present study we investigated 5-hydroxytryptamine (5-HT) and dopamine concentrations in serotonergic and dopaminergic nuclei following chronic administration of L-DOPA to find whether the neurotransmitter synthesis in these brain areas are compensated. (2) Rats were administered L-DOPA (250 mg/kg) and carbidopa (25 mg/kg) daily for 59 and 60 days, and killed on the 60th day, respectively at 24 h and 30 min after the last dose. L-DOPA, norepinephrine, 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), dopamine, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in striatum, nucleus raphe dorsalis (NRD), nucleus accumbens (NAc), substantia nigra, cerebellum, and cortex employing HPLC-electrochemical procedure. (3) Prolonged treatment of L-DOPA caused depression in the animals as revealed in a forced swim test. Serotonin content was significantly decreased in all brain regions studied 30 min after long-term L-DOPA, except in NAc. The cortex and striatum showed lowered levels of this indoleamine 24 h after 59 doses of L-DOPA. Dopamine, HVA, and DOPAC concentrations were significantly higher in all the regions studied after 30 min, and in the cerebellum after 24 h of L-DOPA. The levels of DOPAC were elevated in all the brain areas studied 24 h after prolonged L-DOPA treatment. (4) The present results suggest that long-term L-DOPA treatment results in significant loss of 5-HT in serotonergic and dopaminergic regions of the brain. Furthermore, while L-DOPA metabolism per se was uninfluenced, dopamine synthesis was severely impaired in all the regions. The imbalance of serotonin and dopamine formation may be the cause of overt cognitive, motor, and psychological functional aberrations seen in parkinsonian patients following prolonged L-DOPA treatment.


Parkinson’s disease Forced swim test Dopamine and serotonin synthesis Motor behavior Nucleus raphe 



Anupom Borah is a recipient of Senior Research Fellowship from the Council of Scientific and Industrial Research, Government of India.


  1. Adell A, Celada P, Artigas F (2001) The role of 5-HT1B receptors in the regulation of serotonin cell firing and release in the rat brain. J Neurochem 79:172–182PubMedCrossRefGoogle Scholar
  2. Ahlskog JE, Muenter MD (2001) Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 16:448–458PubMedCrossRefGoogle Scholar
  3. Arai R, Karasawa N, Geffard M, Nagatsu T, Nagatsu I (1994) Immunohistochemical evidence that central serotonin neurons produce dopamine from exogenous L-DOPA in the rat, with reference to the involvement of aromatic L-amino acid decarboxylase. Brain Res 667:295–299PubMedCrossRefGoogle Scholar
  4. Arai R, Karasawa N, Geffard M, Nagatsu I (1995) L-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat. A double-labeling immunofluorescence study. Neurosci Lett 195:195–198PubMedCrossRefGoogle Scholar
  5. Arai R, Karasawa N, Nagatsu I (1996) Aromatic l-amino acid decarboxylase is present in serotonergic fibers of the striatum of the rat. A double-labeling immunofluorescence study. Brain Res 706:177–179PubMedCrossRefGoogle Scholar
  6. Bishop C, Taylor JL, Kuhn DM, Eskow KL, Park JY, Walker PD (2006) MDMA and fenfluramine reduce L-DOPA-induced dyskinesia via indirect 5-HT1A receptor stimulation. Eur J Neurosci 23:2669–2676PubMedCrossRefGoogle Scholar
  7. Brown WD, Taylor MD, Roberts AD, Oakes TR, Schueller MJ, Holden JE, Malischke LM, DeJesus OT, Nickles RJ (1999) Fluorodopa PET shows the nondopaminergic as well as dopaminergic destinations of levodopa. Neurology 53:1212–1218PubMedGoogle Scholar
  8. Carlsson A (1993) Thirty years of dopamine research. Adv Neurol 60:1–10PubMedGoogle Scholar
  9. Cenci MA (2007) Dopamine dysregulation of movement control in L-DOPA-induced dyskinesia. Trends Neurosci 30:236–243PubMedCrossRefGoogle Scholar
  10. Chandra G, Gangopadhyay PK, Senthil Kumar KS, Mohanakumar KP (2006) Acute intranigral homocysteine administration produces stereotypic behavioral changes and striatal dopamine depletion in Sprague–Dawley rats. Brain Res 1075:81–92PubMedCrossRefGoogle Scholar
  11. Chase TN (1998) Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology 50:S17–S25PubMedCrossRefGoogle Scholar
  12. Chesselet MF, Delfs JM (1996) Basal ganglia and movement disorders: an update. Trends Neurosci 19:417–422PubMedGoogle Scholar
  13. Christenson JG, Dairman W, Udenfriend S (1970) Preparation and properties of a homogeneous aromatic L-amino acid decarboxylase from hog kidney. Arch Biochem Biophys 141:356–367PubMedCrossRefGoogle Scholar
  14. Cummings JL, Masterman DL (1999) Depression in patients with Parkinson’s disease. Int J Geriatr Psychiatry 14:711–718PubMedCrossRefGoogle Scholar
  15. Guerra MJ, Liste I, Labandeira-Garcia JL (1998) Interaction between the serotonergic, dopaminergic, and glutamatergic systems in fenfluramine-induced Fos expression in striatal neurons. Synapse 28:71–82PubMedCrossRefGoogle Scholar
  16. Hefti F, Melamed E, Wurtman RJ (1981) The site of dopamine formation in rat striatum after l-DOPA administration. J Pharmacol Exp Ther 217:189–197PubMedGoogle Scholar
  17. Hornykiewicz O (1998) Biochemical aspects of Parkinson’s disease. Neurology 51:S2–S9PubMedGoogle Scholar
  18. Hui JS, Murdock GA, Chung JS, Lew MF (2005) Behavioral changes as side effects of medication treatment for Parkinson’s disease. Adv Neurol 96:114–129PubMedGoogle Scholar
  19. Jaeger CB, Teitelman G, Joh TH, Albert VR, Park DH, Reis DJ (1983) Some neurons of the rat central nervous system contain aromatic L-amino acid decarboxylase but not monoamines. Science 219:1233–1235PubMedCrossRefGoogle Scholar
  20. Kannari K, Tanaka H, Maeda T, Tomiyama M, Suda T, Matsunaga M (2000) Reserpine pretreatment prevents increases in extracellular striatal dopamine following l-DOPA administration in rats with nigrostriatal denervation. J Neurochem 74:263–269PubMedCrossRefGoogle Scholar
  21. Kannari K, Shen H, Arai A, Tomiyama M, Baba M (2006) Reuptake of l-DOPA-derived extracellular dopamine in the striatum with dopaminergic denervation via serotonin transporters. Neurosci Lett 402:62–65PubMedCrossRefGoogle Scholar
  22. Klapdor K, Dulfer BG, Hammann A, Van der Staay FJ (1997) A low-cost method to analyse footprint patterns. J Neurosci Methods 75:49–54PubMedCrossRefGoogle Scholar
  23. Knobelman DA, Kung HF, Lucki I (2000) Regulation of extracellular concentrations of 5-hydroxytryptamine (5-HT) in mouse striatum by 5-HT1A and 5-HT1B receptors. J Pharmacol Exp Ther 292:1111–1117PubMedGoogle Scholar
  24. Kostic VS, Djuricic BM, Covickovic-Sternic N, Bumbasirevic L, Nikolic M, Mrsulja BB (1987) Depression and Parkinson’s disease: possible role of serotonergic mechanisms. J Neurol 234:94–96PubMedCrossRefGoogle Scholar
  25. Lavoie B, Parent A (1990) Immunohistochemical study of the serotoninergic innervation of the basal ganglia in the squirrel monkey. J Comp Neurol 299:1–16PubMedCrossRefGoogle Scholar
  26. Leentjens AF (2004) Depression in Parkinson’s disease: conceptual issues and clinical challenges. J Geriatr Psychiatry Neurol 17:120–126PubMedCrossRefGoogle Scholar
  27. Lemke MR, Fuchs G, Gemende I, Herting B, Oehlwein C, Reichmann H, Reike J, Volkmann J (2004) Depression and Parkinson’s disease. J Neurol 6:24–27Google Scholar
  28. Lopez A, Munoz A, Guerra MJ, Labandeira-Garcia JL (2001) Mechanisms of the effects of exogenous levodopa on the dopamine denervated-striatum. Neuroscience 103:639–651PubMedCrossRefGoogle Scholar
  29. Lovenberg W, Weissbach H, Udenfriend S (1962) Aromatic L-amino acid decarboxylase. J Biol Chem 237:89–93PubMedGoogle Scholar
  30. Maeda T, Nagata K, Yoshida Y, Kannari K (2005) Serotonergic hyperinnervation into the dopaminergic-denervated striatum compensates for dopamine conversion from exogenously administered l-DOPA. Brain Res 1046:230–233PubMedCrossRefGoogle Scholar
  31. Mazzella L, Yahr MD, Marinelli L, Huang N, Moshier E, Di Rocco A (2005) Dyskinesias predict the onset of motor response fluctuations in patients with Parkinson’s disease on l-DOPA monotherapy. Parkinsonism Relat Disord 11:151–155PubMedCrossRefGoogle Scholar
  32. Mehta H, Saravanan KS, Mohanakumar KP (2003) Serotonin synthesis inhibition in olivo-cerebellar system attenuates harmaline-induced tremor in Swiss albino mice. Behav Brain Res 145:31–36PubMedCrossRefGoogle Scholar
  33. Meissner W, Ravenscroft P, Reese R, Harnack D, Morgenstern R, Kupsch A, Klitgaard H, Bioulac B, Gross CE, Bezard E, Boraud T (2006) Increased slow oscillatory activity in substantia nigra pars reticulata triggers abnormal involuntary movements in the 6-OHDA-lesioned rat in the presence of excessive extracellular striatal dopamine. Neurobiol Dis 22:586–598PubMedCrossRefGoogle Scholar
  34. Miller D, Abercrombie ED (1999) Role of high-affinity dopamine uptake and impulse activity in the appearance of extracellular dopamine in striatum after administration of exogenous L-DOPA: studies in intact and 6-hydroxydopamine-treated rats. J Neurochem 72:1516–1522PubMedCrossRefGoogle Scholar
  35. Mura A, Jackson D, Manley MS, Young SJ, Groves PM (1995) Aromatic L-amino acid decarboxylase immunoreactive cells in the rat striatum: a possible site for the conversion of exogenous L-DOPA to dopamine. Brain Res 704:51–60PubMedCrossRefGoogle Scholar
  36. Muralikrishnan D, Mohanakumar KP (1998) Neuroprotection by bromocriptine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice. FASEB J 12:905–912PubMedGoogle Scholar
  37. Nicholson SL, Brotchie JM (2002) 5-hydroxytryptamine (5-HT, serotonin) and Parkinson’s disease—opportunities for novel therapeutics to reduce the problems of levodopa therapy. Eur J Neurol 9:1–6PubMedCrossRefGoogle Scholar
  38. Nutt JG (1990) Levodopa-induced dyskinesia: review, observations, and speculations. Neurology 40:340–345PubMedGoogle Scholar
  39. Palkovits M, Brownstein MJ (1983) Brain microdissection techniques. John Wiley and Sons, New YorkGoogle Scholar
  40. Poewe W (2003) Psychosis in Parkinson’s disease. Mov Disord 6:S80–S87CrossRefGoogle Scholar
  41. Porsolt RD, Pichon LM, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732PubMedCrossRefGoogle Scholar
  42. Rozas G, Liste I, Guerra MJ, Labandeira-Garcia JL (1998) Sprouting of the serotonergic afferents into striatum after selective lesion of the dopaminergic system by MPTP in adult mice. Neurosci Lett 245:151–154PubMedCrossRefGoogle Scholar
  43. Steinbusch HWM (1984) Serotonin-immunoreactive neurons and their projections in the CNS. In: Bjorklund A, Hokfelt T, Kuhar MJ (eds) Handbook of chemical neuroanatomy, vol. 3, classical transmitter receptors in the CNS, part II. Elsevier Sciences Publishers, Amsterdam, pp. 68–125Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Division of Cell Biology and Physiology, Laboratory of NeuroscienceIndian Institute of Chemical BiologyKolkataIndia

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