Experimental Brain Research

, Volume 93, Issue 2, pp 259–270

The vigilance-promoting drug modafinil counteracts the reduction of tyrosine hydroxylase immunoreactivity and of dopamine stores in nigrostriatal dopamine neurons in the male rat after a partial transection of the dopamine pathway

  • A. Ueki
  • L. Rosén
  • B. Andbjer
  • U. B. Finnman
  • U. Altamimi
  • A. M. Janson
  • M. Goldstein
  • L. F. Agnati
  • K. Fuxe
Article

Abstract

We studied the ability of the vigilance-promoting drug modafinil to modulate the anterograde and retrograde changes in tyrosine hydroxylase (TH) immunoreactivity and in dopamine (DA) stores in the nigro-neostriatal DA neurons, following a partial hemitransection of this ascending DA system, using a combined morphometrical, biochemical and behavioural analysis. Modafinil was given daily i.p. in doses of 10–100 mg/kg, starting 15 min after the lesion, and the partially hemitransected rats were killed 2 weeks later. Changes in TH-immunoreactive nerve cell bodies and nerve terminals induced by the partial hemitransection were studied in the substantia nigra and neostriatum in combination with image analysis. The substantia nigra and neostriatum were also subjected to biochemical analysis of DA, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels. Modafinil treatment dose-dependently (10–100 mg/kg) counteracted the hemitransection-induced disappearance of nigral TH-immunoreactive nerve cell body profiles and neostriatal TH-immunoreactive nerve terminal profiles. A 2-week treatment with 100 mg/kg of modafinil also counteracted the hemitransection-induced depletion of DA stores in the neostriatum and the ventral midbrain. Moreover, the repeated daily treatment with modafinil (100 mg/kg) protected against the hemitransection-induced disappearance of striatal 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and noradrenaline levels. Striatal DA function was analysed by studying apomorphine-induced (1 mg/kg, s.c.) ipsilateral rotational behaviour 4 and 11 days after the operation. A marked dose-dependent reduction of ipsilateral rotational behaviour was demonstrated after the daily modafinil treatment in the partially hemitransected rats. In another model involving unilateral nigral microinjections of 6-hydroxydopamine, acute (one single dose) modafinil (100 mg/kg) did not affect the contralateral rotational behaviour induced by apomorphine (0.05 mg/kg s.c.), when given 30 min before the apomorphine. Taken together, morphological, neurochemical and behavioural evidence has been obtained that anterograde and retrograde changes induced in the DA stores and TH immunoreactivity of the nigro-neostriatal DA neurons by a partial hemitransection are counteracted by modafinil in a dose dependent way with 100 mg/kg producing a significant protective action against impairment of DA transmission. The results of this study open up the possibility that modafinil may protect against the anterograde and retrograde degeneration of nigrostriatal DA neurons seen after mechanically induced injury.

Key words

Dopamine Substantia nigra Striatum Hemitransection Rat 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Agnati LF, Fuxe K, Colza L, Benfenati F, Cavicchioli L, Toffano G, Goldstein M (1983) Gangliosides increase the survival of lesioned nigral dopamine neurons and favour the recovery of dopaminergic synaptic function in striatum of rats by collateral sprouting. Acta Physiol Scand 199:347–363Google Scholar
  2. Agnati LF, Fuxe K, Zoli M, Zini I, Toffano G, Ferraguti F (1986) A corrrelation analysis of the regional distribution of central enkephalin and b-endorphin immunoreactive terminals and of opiate receptors in the adult and old male rats. Evidence for the existence of two main types of communication in the central nervous system: the volume transmission and the wiring transmission. Acta Physiol Scand 128:201–207Google Scholar
  3. Agnati LF, Fuxe K, Zoli M, Zini I, Härfstrand A, Toffano G, Goldstein M (1988) Morphometrical and microdensitometrical studies on phenylethanolamine-N-methyltransferase and neuropeptide Y immunoreactive neurons in the rostral medulla oblongata of the adult and old male rat. Neuroscience 26:461–478Google Scholar
  4. Bastuji H, Jouvet M (1988) Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiatry 12:695–700Google Scholar
  5. Beal MF (1992) Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann Neurol 31:119–130.Google Scholar
  6. Bean AJ, Elde R, Cao Y, Oellig C, Tamminga C, Goldstein M, Petterson R, Hökfelt T (1991) Expression of acidic and basic fibroblast growth factor in the substantia nigra of rat, monkey and human. Proc Natl Acad Sci USA 88:10237–10241Google Scholar
  7. Chan P, DeLanney LE, Irwin I, Langston JW, Di Monte D (1991) Rapid ATP loss caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mouse brain. J Neurochem 57:348–351Google Scholar
  8. Cintra A, Cao Y, Oellig C, Tinner B, Bortolotti F, Goldstein M, Petterson RF, Fuxe K (1991) Basic FGF is present in dopaminergic neurons of the ventral midbrain of the rat. Neuroreport 2:597–600Google Scholar
  9. Duteil J, Rambert FA, Pessonnier J, Hermant JF, Gombert R, Assous E (1990) Central alpha1-adrenergic stimulation in relation to behaviour stimulating effect of modafinil; studies with experimental animals. Eur J Pharmacol 180:49–58Google Scholar
  10. Fuxe K, Hökfelt T, Ungerstedt U (1970) Morphological and functional aspects of central monoamine neurons. Int Rev Neurobiol 13:93–126Google Scholar
  11. Fuxe K, Cintra A, Agnati LF, Härfstrand A, Goldstein M (1988) Studies on the relationship of tyrosine hydroxylase, dopamine cyclic AMP-regulated phosphoprotein-32 immunoreactive neuronal structures and D1 receptor antagonist binding sites in various brain regions of the male rat mismatches indicate a role of D1 receptors in volume transmission. Neurochem Int 13:179–197Google Scholar
  12. Fuxe K, Kurosawa M, Cintra A, Goiny M, Hallström {8f}, Rosén L, Ungerstedt U, Agnati LF (1991) Endothelin-1 induced lesions in the brain as a new model of focal ischemia. Methods Neurosci 7:256–282Google Scholar
  13. Fuxe K, Janson AM, Rosén L, Finnman U-B, Tanganelli S, Morari M, Goldstein M, Agnati LF (1992) Evidence for a protective action of the vigilance promoting drug Modafinil on the MPTP induced degeneration of the nigrostriatal dopamine neurons in the black mouse: an immunocytochemical and biochemical analysis. Exp Brain Res 88:117–130Google Scholar
  14. Gundersen HJG, Bagger P, Bendtsen TF, Evans SM, Korbo L, Marcussen N, Møller A, Nielsen K, Nyengaard JR, Pakkenberg B, Sorensen FB, Vesterby A, West M (1988) The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. Review article. APMIS 96:857–881Google Scholar
  15. Hagg T, Manthorpe M, Vahlsing HL, Varon S (1988) Delayed treatment with nerve growth factor reverses the apparent loss of cholinergic neuron after acute brain damage. Exp Neurol 101:303–312Google Scholar
  16. Hall ED (1992) The neuroprotective pharmacology of methylprednisolone. J Neurosurg 76:13–22Google Scholar
  17. Hermant J-F, Rambert FA, Duteil J (1991) Awakening properties of modafinil: effect on nocturnal activity in monkeys (Macaca mulatta) after acute and repeated administration. Psychopharmacology 103:28–32Google Scholar
  18. Hollander M, Wolfe DA (1973) Nonparametric statistical methods. Wiley, New YorkGoogle Scholar
  19. Janson AM, Fuxe K, Agnati LF, Kitayama I, Härstrand A, Andersson K, Goldstein M (1988) Chronic nicotine treatment counteracts the disappearance of tyrosine hydroxylase immunoreactive nerve cell bodies, dendrites and terminals in the meso-striatal dopamine system of the male rat after partial hemitransection. Brain Res 455:332–345Google Scholar
  20. Jenner P (1989) Clues to the mechanism underlying dopamine cell death in Parkinson's disease. J Neurol Neurosurg Psychiatry [Suppl] 22–28Google Scholar
  21. Johannessen JN (1991) A model of chronic neurotoxicity: long-term retention of the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) within catecholaminergic neurons. Neurotoxicology 12:285–302Google Scholar
  22. Keller R, Oke A, Mefford I, Adams RN (1976) The use of liquid chromatographic analysis of catecholamines routine assay of regional brain mapping. Life Sci 19:995–1004Google Scholar
  23. Krauth J (1988) Distribution-free statistics: an application-oriented approach. Elsevier, Amsterdam New YorkGoogle Scholar
  24. Kromer LF (1987) Nerve growth factor treatment after brain injury prevents neuronal death. Science 235:214–216Google Scholar
  25. Luthman J (1989) Neonatal dopamine lesions: morphological, biochemical and behavioural characterization. Thesis ISBN 91–7900–864-X, Karolinska Institute, StockholmGoogle Scholar
  26. Markey KA, Kondo S, Shenkman L, Goldstein M (1980) Purification and characterization of tyrosine hydroxylase from a clonal chromocytoma cell line. Mol Pharmacol 17:79–85PubMedGoogle Scholar
  27. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, New York LondonGoogle Scholar
  28. Reis DJ, Gilad G, Pickel VM, Joh TH (1978) Reversible changes in the activities and amounts of tyrosine hydroxylase in dopamine neurons of the substantia nigra in response to axonal injury as studied by immunochemical and immunocytochemical methods. Brain Res 144:325–342Google Scholar
  29. Shapira AH, Mann VM, Cooper JM, Dexter D, Daniel SE, Jenner P, Clark JB, Marsden CD (1990) Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson's disease. J Neurochem 55:2142–2145Google Scholar
  30. Tanganelli S, Fuxe K, Ferraro L, Janson AM, Bianchi C (1992) Inhibitory effects of the psychoactive drug Modafinil on γ- aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea-pig. Possible involvement of 5-hydroxytryptamine mechanisms. Naunyn Schmiedebergs Arch Pharmacol 345:461–465Google Scholar
  31. Ueki A, Rosén L, Andbjer B, Agnati LF, Hallström A, Goiny M, Tanganelli S, Ungerstedt U, Fuxe K (dy1993) Evidence for a protective action of vigilance promoting drug modafinil against striatal ischemic injury induced by endothelin-1 in the rat. Exp Brain ResGoogle Scholar
  32. Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5:107–110CrossRefPubMedGoogle Scholar
  33. Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand [Suppl] 367:69–93PubMedGoogle Scholar
  34. Ungerstedt U, Arbuthnott GW (1970) Quantitative recording of rotation behaviour in rats after 6-OH dopamine lesions of the nigro-striatal dopamine systems. Brain Res 24:485–493CrossRefPubMedGoogle Scholar
  35. Zoli M, Zini I, Agnati LF, Guidolin D, Ferraguti F, Fuxe K (1990) Aspects of neural plasticity in the central nervous system. I. Computer-assisted image analysis methods. Neurochem Int 16:383–418Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • A. Ueki
    • 1
  • L. Rosén
    • 1
  • B. Andbjer
    • 1
  • U. B. Finnman
    • 1
  • U. Altamimi
    • 1
  • A. M. Janson
    • 1
  • M. Goldstein
    • 2
  • L. F. Agnati
    • 3
  • K. Fuxe
    • 1
  1. 1.Department of Histology and NeurobiologyKarolinska InstitutetStockholmSweden
  2. 2.New York University, School of Medicine, Medical CenterNew YorkUSA
  3. 3.Department of Human PhysiologyUniversity of ModenaModenaItaly

Personalised recommendations