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Electrophysiological and Neurochemical Characterization of 7-Nitroindazole and Molsidomine Acute and Sub-Chronic Administration Effects in the Dopaminergic Nigrostrial System in Rats

  • Vincenzo Di Matteo
  • Massimo Pierucci
  • Arcangelo Benigno
  • Gergely Orbán
  • Giuseppe Crescimanno
  • Ennio Esposito
  • Giuseppe Di GiovanniEmail author
Chapter
Part of the Journal of Neural Transmission. Supplementa book series (NEURALTRANS, volume 73)

Abstract

Nitric oxide (NO) plays an important role in the integration of information processed by the basal ganglia nuclei. Accordingly, considerable evidence has emerged indicating a role for NO in pathophysiological conditions such as Parkinson’s disease (PD) and other neurodegenerative disorders. Despite these recent advances, the nitrergic modulation of the dopamine (DA) nigrostriatal system is still unclear. In order to fill this gap, in this study we used in vivo electrophysiology and ex vivo neurochemical analysis to further investigate the effect of NO signaling in rat substantia nigra pars compacta (SNc) and the striatum. Acute and subchronic (4 days) pharmacological manipulation of the NO system using 7-nitroindazole (7-NI, 50 mg kg−1 i.p.) and molsidomine (MOL, 40 mg kg−1 i.p.) treatment caused significant changes in both DA SNc neurons electrophysiological properties and striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. It is worth noting that acute inhibition of NO production decreased DA nigrostriatal neurotransmission while its subchronic inhibition was instead excitatory. Thus, a crucial role for NO in the modulation of nigrostriatal DA function is suggested together with a potential role for inhibitors of NO sythase in the treatment of PD.

Keywords

Cells-per-track Dopamine Extracellular recording HPLC Nitric oxide Parkinson’s disease 

Abbreviations

6-OHDA

6-hydroxydopamine

7-NI

7-nitroindazole

ACh

Acetylcholine

BBB

Blood brain barrier

DA

Dopamine

DOPAC

3,4-dihydroxyphenylacetic acid

l-ARG

l-Arginine

l-NAME

N-ω-nitro-l-arginine methyl ester

l-NOARG

l-nitro-arginine

MAO

Monoamine oxidase

MOL

Molsidomine

NNLA

N-nitro-l-arginine

nNOS

Neuronal NO synthase

NO

Nitric oxide

oPFC

Orbital prefrontal cortex

PD

Parkinson’s disease

POPAC

Dihydroxyphenilacetic acid

PPT

Pedunculopontine tegmental nucleus

SIN-1

3-morpholinosydnonomine

SNc

Substantia nigra pars compacta

VTA

Ventral tegmental area

Notes

Acknowledgments

This study was supported in part by Ateneo di Palermo research funding, project ORPA068JJ5, coordinator G. D.; G. O. was supported by an Italian Ministry of the University and Scientific Research fellowship (Tutor: G. D.).

References

  1. Bian K, Murad F (2003) Nitric oxide (NO)-biogeneration, regulation, and relevance to human diseases. Front Biosci 8:264–278CrossRefGoogle Scholar
  2. Bishnoi M, Chopra K, Kulkarni SK (2009) Co-administration of nitric oxide (NO) donors prevents haloperidol-induced orofacial dyskinesia, oxidative damage and change in striatal dopamine levels. Pharmacol Biochem Behav 91:423–429CrossRefPubMedGoogle Scholar
  3. Boger RH, Bode-Boger SM, Gerecke U, Frolich JC (1994) Long-term administration of L-arginine, L-NAME and the exogenous NO donor molsidomine modulates urinary nitrate and cGMP excretion in rats. Cardiovasc Res 28:494–499CrossRefPubMedGoogle Scholar
  4. Boireau A, Dubedat P, Bordier F, Imperato A, Moussaoui S (2000) The protective effect of riluzole in the MPTP model of Parkinson’s disease in mice is not due to a decrease in MPP(+) accumulation. Neuropharmacology 39:1016–1020CrossRefPubMedGoogle Scholar
  5. Bredt DS, Hwang PM, Snyder SH (1990) Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347(6295):768–770CrossRefPubMedGoogle Scholar
  6. Bunney BS, Walters JR, Roth RH, Aghajanian GK (1973) Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single cell activity. J Pharmacol Exp Ther 185(3):560–571PubMedGoogle Scholar
  7. Büyükuysal RL (1997) Effect of nitric oxide donors on endogenous dopamine release from striatal slices. I. Requirement of antioxidants in the medium. Fundam Clin Pharmacol 11:519–527CrossRefPubMedGoogle Scholar
  8. Castagnoli K, Palmer S, Anderson A, Bueters T, Castagnoli N Jr (1997) The neuronal nitric oxide synthase inhibitor 7-nitroindazole also inhibits the monoamine oxidase-B-catalyzed oxidation of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Chem Res Toxicol 10:364–368CrossRefPubMedGoogle Scholar
  9. Cox BA, Johnson SW (1998) Nitric oxide facilitates N-methyl- D-aspartate-induced burst firing in dopamine neurons from rat midbrain slices. Neurosci Lett 255(3):131–134CrossRefPubMedGoogle Scholar
  10. Del Bel EA, Guimarães FS (2000) Sub-chronic inhibition of nitricoxide synthesis modifies haloperidol-induced catalepsy and the number of NADPH-diaphorase neurons in mice. Psychopharmacology 147:356–361CrossRefPubMedGoogle Scholar
  11. Del Bel EA, da Silva CA, Guimarães FS (1998) Catalepsy induced by nitric oxide synthase inhibitors. Gen Pharmacol 30:245–248PubMedGoogle Scholar
  12. Del Bel EA, Souza AS, Guimarães FS, da-Silva CA, Nucci-da-Silva LP (2002) Motor effects of acute and chronic inhibition of nitric oxide synthesis in mice. Psychopharmacology 161:32–37CrossRefPubMedGoogle Scholar
  13. Del Bel EA, da Silva CA, Guimarães FS, Bermudez-Echeverry M (2004) Catalepsy induced by intra-striatal administration of nitric oxide synthase inhibitors in rats. Eur J Pharmacol 485:175–181CrossRefPubMedGoogle Scholar
  14. Del Bel EA, Guimarães FS, Bermudez-Echeverry M, Gomes MZ, Schiaveto-de-souza A, Padovan-Neto FE, Tumas V, Barion- Cavalcanti AP, Lazzarini M, Nucci-da-Silva LP, de Paula-Souza D (2005) Role of nitric oxide on motor behaviour. Cell Mol Neurobiol 25:371–392CrossRefPubMedGoogle Scholar
  15. Del Bel E, Bermúdez-Echeverry M, Salum C, Raisman-Vozari R (2007) Nitric oxide system and basal ganglia physiopathology. In: Di Giovanni G (ed) The basal ganglia pathophysiology: recent advances. Transworld Research Network, Kerala, IndiaGoogle Scholar
  16. Del Bel E, Guimarães F, Joca S, Echeverry M, Ferreira F (2008) Tolerance to the cataleptic effect that follows repeated nitric oxide synthase inhibition may be related to functional enzymatic recovery. J Psychopharmacol published on October 6, 2008 as doi:10.1177/0269881108097717Google Scholar
  17. Desvignes C, Bert L, Vinet L, Denoroy L, Renaud B, Lambás-Señas L (1999) Evidence that the neuronal nitric oxide synthase inhibitor 7-nitroindazole inhibits monoamine oxidase in the rat: in vivo effects on extracellular striatal dopamine and 3, 4-dihydroxyphenylacetic acid. Neurosci Lett 264(1–3):5–8CrossRefPubMedGoogle Scholar
  18. Di Giovanni G (2007) The Basal Ganglia Pathophysiology: Recent Advances. Transworld Research Network, Kerala, IndiaGoogle Scholar
  19. Di Giovanni G, Ferraro G, Sardo P, Galati S, Esposito E, La Grutta V (2003) Nitric oxide modulates striatal neuronal activity via soluble guanylyl cyclase: an in vivo microiontophoretic study in rats. Synapse 48(2):100–107CrossRefPubMedGoogle Scholar
  20. Di Giovanni G, Ferraro G, Sardo P, Di Maio R, Carlatti F, La Grutta V (2006) Microiontophoretic evidence that nitric oxide alters spontaneous activity of the substantia nigra pars reticulata neurons in the rat. Acta Physiol 188(Suppl. 652):P184Google Scholar
  21. Di Giovanni G, Shi W-X (2009) Effects of Scopolamine on Dopamine Neurons in the Substantia Nigra: Role of the Pedunculopontine Tegmental Nucleus. Synapse 63(8):673–680CrossRefPubMedGoogle Scholar
  22. Di Matteo V, Benigno A, Pierucci M, Giuliano DA, Crescimanno G, Esposito E, Di Giovanni G (2006) 7-nitroindazole protects striatal dopaminergic neurons against MPP+-induced degeneration: an in vivo microdialysis study. Ann NY Acad Sci 1089:462–471CrossRefPubMedGoogle Scholar
  23. Di Matteo V, Pierucci M, Esposito E, Benigno A, Crescimanno G, Di Giovanni G (2009) Involvement of nitric oxide in 6-OHDA-induced neurodegeneration: An ex vivo study. Ann NY Acad Sci 1155:316–323CrossRefPubMedGoogle Scholar
  24. Egberongbe YI, Gentleman SM, Falkai P, Bogerts B, Polak JM, Roberts GW (1994) The distribution of nitric oxide synthase immunoreactivity in the human brain. Neuroscience 59(3):561–578CrossRefPubMedGoogle Scholar
  25. Esposito E, Di Matteo V, Di Giovanni G (2007) Death in the substantia nigra: a motor tragedy. Expert Rev Neurother 7:7677–7697CrossRefGoogle Scholar
  26. Eve DJ, Nisbet AP, Hewson KAE, EL DSE, Lees AJ, Marsden CD, Foster OJ (1998) Basal ganglia neuronal nitric oxide synthase mRNA expression in Parkinson’s disease. Brain Res Mol Brain Res 63(1):62–71CrossRefPubMedGoogle Scholar
  27. Feifer A, Carrier S (2008) Pharmacotherapy for erectile dysfunction. Expert Opin Investig Drugs 17:679–690CrossRefPubMedGoogle Scholar
  28. Floresco SB, West AR, Ash B, Moore H, Grace AA (2003) Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat Neurosci 6(9):968–973CrossRefPubMedGoogle Scholar
  29. Galati S, D’angelo V, Scarnati E, Stanzione P, Martorana A, Procopio T, Sancesario G, Stefani A (2008) In vivo electrophysiology of dopamine-denervated striatum: focus on the nitric oxide/cGMP signaling pathway. Synapse 62(6):409–420CrossRefPubMedGoogle Scholar
  30. Garthwaite J, Boulton CL (1995) Nitric oxide signaling in the central nervous system. Annu Rev Physiol 57:683–706CrossRefPubMedGoogle Scholar
  31. Gomes MZ, Raisman-Vozari R, Del Bel EA (2008) A nitric oxide synthase inhibitor decreases 6-hydroxydopamine effects on tyrosine hydroxylase and neuronal nitric oxide synthase in the rat nigrostriatal pathway. Brain Res 1203:160–169CrossRefPubMedGoogle Scholar
  32. Grace AA, Floresco SB, Goto Y, Lodge DJ (2007) Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci 30(5):220–227CrossRefPubMedGoogle Scholar
  33. Guevara-Guzman R, Emson PC, Kendrick KM (1994) Modulation of in vivo striatal transmitter release by nitric oxide and cyclic-GMP. J Neurochem 62:807–810CrossRefPubMedGoogle Scholar
  34. Koylu EO, Kanit L, Taskiran D, Dagci T, Balkan B, Pogun S (2005) Effects of nitric oxide synthase inhibition on spatial discrimination learning and central DA2 and mACh receptors. Pharmacol Biochem Behav 81:32–40CrossRefPubMedGoogle Scholar
  35. Krzaścik P, Kostowski W (1997) Nitric oxide donors antagonize N-nitro-L-arginine and haloperidol catalepsy: potential implication for the treatment of Parkinsonism? Pol J Pharmacol 49(4):263–266PubMedGoogle Scholar
  36. Leontovich TA, Mukhina YK, Fedorov AA (2004) Neurons of the basal ganglia of the human brain (striatum and basolateral amygdala) expressing the enzyme NADPH-d. Neurosci Behav Physiol 34(3):277–286CrossRefPubMedGoogle Scholar
  37. Liu X, Buffington JA, Tjalkens RB (2005) NF-kappaB-dependent production of nitric oxide by astrocytes mediates apoptosis in differentiated PC12 neurons following exposure to manganese and cytokines. Brain Res Mol Brain Res 141(1):39–47CrossRefPubMedGoogle Scholar
  38. Low SY (2005) Application of pharmaceuticals to nitric oxide. Mol Aspects Med 26(1–2):97–138CrossRefPubMedGoogle Scholar
  39. Maccario M, Oleandri SE, Procopio M, Grottoli S, Avogadri E, Camanni F (1997) Comparisons among the effects of arginine, a nitric oxide precursor, isosorbide dinitrate and molsidomine, two nitric oxide donors on hormonal secretions and blood pressure in man. J Endocrinol Invest 20:488–492PubMedGoogle Scholar
  40. Marras R, Martins AP, Del Bel EA, Guimarães FS (1995) L-NOARG, an inhibitor of nitric oxide synthase induces catalepsy in mice. NeuroReport 7:158–160PubMedGoogle Scholar
  41. Moore PK, Babbedge RC, Wallace P, Gaffen ZA, Hart SL (1993) 7-Nitro indazole, an inhibitor of nitric oxide synthase, exhibits anti-nociceptive activity in the mouse without increasing blood pressure. Br J Pharmacol 108:296–297PubMedGoogle Scholar
  42. Nisbet AP, Foster OJ, Kingsbury A, Lees AJ, Marsden CD (1994) Nitric oxide synthase mRNA expression in human subthalamic nucleus, striatum and globus pallidus: implications for basal ganglia function. Brain Res Mol Brain Res 22(1–4):329–332CrossRefPubMedGoogle Scholar
  43. Nitz R, Fiedler V (1987) Molsidomine: alternative approaches to treat myocardial ischemia. Pharmacotherapy 7:28–37PubMedGoogle Scholar
  44. Ondracek JM, Dec A, Hoque KE, Lim SA, Rasouli G, Indorkar RP, Linardakis J, Klika B, Mukherji SJ, Burnazi M, Threlfell S, Sammut S, West AR (2008) Feed-forward excitation of striatal neuron activity by frontal cortical activation of nitric oxide signaling in vivo. Eur J Neurosci 27(7):1739–1754CrossRefPubMedGoogle Scholar
  45. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic, New YorkGoogle Scholar
  46. Rigamonti AE, Cella SG, Cavallera GM, Deghenghi R, Locatelli V, Pitsikas N, Muller EE (2001) Contrasting effects of nitric oxide on food intake and GH secretion stimulated by a GH-releasing peptide. Eur J Endocrinol 144:155–162CrossRefPubMedGoogle Scholar
  47. Rosenkranz B, Winkelmann BR, Parnham MJ (1996) Clinical pharmacokinetics of molsidomine. Clin Pharmacokinet 30:372–384CrossRefPubMedGoogle Scholar
  48. Sammut S, Dec A, Mitchell D, Linardakis J, Ortiguela M, West AR (2006) Phasic dopaminergic transmission increases NO efflux in the rat dorsal striatum via a neuronal NOS and a dopamine D(1/5) receptor-dependent mechanism. Neuropsychopharmacology 31(3): 493–505CrossRefPubMedGoogle Scholar
  49. Sammut S, Bray KE, West AR (2007) Dopamine D2 receptor-dependent modulation of striatal NO synthase activity. Psychopharmacology (Berl) 191(3):793–803CrossRefGoogle Scholar
  50. Sardo P, Ferraro G, Di Giovanni G, Galati S, La Grutta V (2002) Inhibition of nitric oxide synthase influences the activity of striatal neurons in the rat. Neurosci Lett 325(3):179–182CrossRefPubMedGoogle Scholar
  51. Sardo P, Ferraro G, Di Giovanni G, La Grutta V (2003) Nitric oxide-induced inhibition on striatal cells and excitation on globus pallidus neurons: a microiontophoretic study in the rat. Neurosci Lett 343(2):101–104CrossRefPubMedGoogle Scholar
  52. Sardo P, Carletti F, D’Agostino S, Rizzo V, Ferraro G (2006) Effects of nitric oxide-active drugs on the discharge of subthalamic neurons: microiontophoretic evidence in the rat. Eur J Neurosci 24(7): 1995–2002CrossRefPubMedGoogle Scholar
  53. Schilström B, Mameli-Engvall M, Rawal N, Grillner P, Jardemark K, Svensson TH (2004) Nitric oxide is involved in nicotine-induced burst firing of rat ventral tegmental area dopamine neurons. Neuroscience 125:957–964CrossRefPubMedGoogle Scholar
  54. Shi WX, Smith PL, Pun CL, Millet B, Bunney BS (1997) D1–D2 interaction in feedback control of midbrain dopamine neurons. J Neurosci 17(20):7988–7994PubMedGoogle Scholar
  55. Shim SS, Bunney BS, Shi WX (1996) Effects of lesions in the medial prefrontal cortex on the activity of midbrain dopamine neurons. Neuropsychopharmacology 15(5):437–441CrossRefPubMedGoogle Scholar
  56. Silva MT, Rose S, Hindmarsh JG, Aislaitner G, Gorrod JW, Moore PK, Jenner P, Marsden CD (1995) Increased striatal dopamine efflux in vivo following inhibition of cerebral nitric oxide synthase by the novel monosodium salt of 7-nitro indazole. Br J Pharmacol 114(2):257–258PubMedGoogle Scholar
  57. Silva MT, Rose S, Hindmarsh JG, Jenner P (2003) Inhibition of neuronal nitric oxide synthase increases dopamine efflux from rat striatum. J Neural Transm 110(4):353–362CrossRefPubMedGoogle Scholar
  58. Simola N, Morelli M, Carta AR (2007) The 6-hydroxydopamine model of Parkinson’s disease. Neurotox Res 11:151–167CrossRefPubMedGoogle Scholar
  59. Southan GJ, Szabo C (1996) Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem Pharmacol 51:383–394CrossRefPubMedGoogle Scholar
  60. Sugaya K, McKinney M (1994) Nitric oxide synthase gene expression in cholinergic neurons in the rat brain examined by combined immunocytochemistry andin situ hybridization histochemistry. Mol Brain Res 23:111–125CrossRefPubMedGoogle Scholar
  61. Thatcher GR, Bennett BM, Reynolds JN (2006) NO chimeras as therapeutic agents in Alzheimer’s disease. Curr Alzheimer Res 3:237–245CrossRefPubMedGoogle Scholar
  62. Thomas B, Saravanan KS, Mohanakumar KP (2008) In vitro and in vivo evidences that antioxidant action contributes to the neuroprotective effects of the neuronal nitric oxide synthase and monoamine oxidase-B inhibitor, 7-nitroindazole. Neurochem Int 52:990–1001CrossRefPubMedGoogle Scholar
  63. Trabace L, Kendrick KM (2000) Nitric oxide can differentially modulate striatal neurotransmitter concentrations via soluble guanylate cyclase and peroxynitrite formation. J Neurochem 75(4):1664–1674CrossRefPubMedGoogle Scholar
  64. Vincent SR, Kimura H (1992) Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience 46(4):755–784CrossRefPubMedGoogle Scholar
  65. West AR, Grace AA (2000) Striatal nitric oxide signaling regulates the neuronal activity of midbrain dopamine neurons in vivo. J Neurophysiol 83(4):1796–1808PubMedGoogle Scholar
  66. West AR, Galloway MP, Grace AA (2002) Regulation of striatal dopamine neurotransmission by nitric oxide: effector pathways and signaling mechanisms. Synapse 44(4):227–245CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag/Wien Printed in Germany 2009

Authors and Affiliations

  • Vincenzo Di Matteo
    • 1
  • Massimo Pierucci
    • 1
  • Arcangelo Benigno
    • 2
  • Gergely Orbán
    • 2
  • Giuseppe Crescimanno
    • 2
  • Ennio Esposito
    • 1
  • Giuseppe Di Giovanni
    • 2
    Email author
  1. 1.Istituto di Ricerche Farmacologiche “Mario Negri”Consorzio Mario Negri SudS. Maria ImbaroItaly
  2. 2.Dipartimento di Medicina SperimentaleSezione di Fisiologia Umana “G. Pagano”, Università degli Studi di PalermoPalermoItaly

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