Experimental Brain Research

, Volume 88, Issue 1, pp 117–130 | Cite as

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

  • K. Fuxe
  • A. M. Janson
  • L. Rosén
  • U. -B. Finnman
  • S. Tanganelli
  • M. Morari
  • M. Goldstein
  • L. F. Agnati
Article

Summary

Based on the observations that the psychostimulant drug amphetamine in combination with physiotherapy can promote recovery of brain function after brain injury, we have studied the ability of the vigilance promoting drug Modafinil to counteract 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP)-induced degeneration of the nigrostriatal dopamine (DA) neurons of the black mouse. MPTP was given s.c. in a dose of 40 mg/kg and the mice were sacrificed 2 weeks later. The effects of acute and chronic treatment with Modafinil were studied on MPTP-induced DA neurotoxicity. The substantia nigra and neostriatum were taken to both biochemical and histochemical analysis of presynaptic parameters of the nigrostriatal DA neurons, the latter in combination with image analysis. In separate experiments in rats in vivo tests for DA uptake blocking activity were made using intrastriatal microdialysis to study superfusate levels of DA and its metabolites and the 4-α-dimethylmetatyramine (H77/77) model to test for a possible ability of Modafinil to protect against H77/77-induced depletion of forebrain DA stores. Chronic treatment with Modafinil in doses of 10 to 100 mg/kg counteracted the MPTP-induced disappearance of nigral TH IR nerve cell body profiles and neostriatal TH IR nerve terminal profiles as evaluated after 2 weeks with image analysis. Chronic treatment with Modafinil (10–100 mg/kg) also dose-dependently counteracted the MPTP-induced disappearance of striatal DA uptake binding sites as evaluated at the same time interval. Also in the dose range 10–100 mg/kg Modafinil counteracts the MPTP-induced depletion of DA stores both in the neostriatum and the substantia nigra. In the acute experiments Modafinil (30 mg/kg) protected against the MPTP-induced depletion of striatal DA, dihydrophenylacetic acid (DOPAC) and homovanillic acid (HVA) levels both when given 15 min before, at the same time and 3 h following the MPTP injection. In the substantia nigra, however, these protective actions of Modafinil were only observed when the drug was coadministered with MPTP. Experiments with microdialysis in intact rats failed to demonstrate any increases of superfusate DA levels in neostriatum with 30 mg/kg of Modafinil. Modafinil in high doses of 2 × 50 mg/kg, however, significantly counteracted the H77/77 induced DA depletion of striatal DA stores. Thus, morphological and biochemical evidence has been obtained that Modafinil in the dose range 10–100 mg/kg protects against MPTP-induced degeneration of the nigrostriatal DA neurons of the black mouse. The results also indicate that the protective action of Modafinil is not caused by monoamine oxidase inhibition or by DA uptake inhibition, although the latter action may contribute in the highest dose used (100 mg/kg). Instead, it is hypothesized that its protective action may be related to actions on GABAergic mechanisms as evidenced by reduced cortical GABA outflow in doses of 3–30 mg/kg (Tanganelli et al. 1991) and/or to other unknown mechanisms.

Key words

MPTP Dopamine Degeneration Mouse Protection Uptake Immunocytochemistry Image analysis Biochemistry Substantia nigra Neostriatum 

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References

  1. Agnati LF, Fuxe K, Zoli M, Zini I, Härfstrand A, Toffano G, Goldstein M (1988a) 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 26:461–478CrossRefPubMedGoogle Scholar
  2. Agnati LF, Zini I, Zoli M, Fuxe K, Merlo Pich E, Grimaldi R, Toffano G, Goldstein M (1988b) Regeneration in the central nervous system: concepts and facts. In: Symon L et al (eds) Advances and technical standars in neurosurgery, vol 16. Springer, Vienna, pp 3–50Google Scholar
  3. Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 80:4546–4550PubMedGoogle Scholar
  4. Carlsson A, Corrodi H, Fuxe K, Hökfelt T (1969) Effects of some antidepressant drugs on the depletion of intraneuronal brain catecholamine stores caused by 4,α-dimethyl-meta-tyramine. Eur J Pharmacol 5:367–373CrossRefPubMedGoogle Scholar
  5. Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, Kopin IJ (1979) Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiat Res 1:249–254CrossRefGoogle Scholar
  6. Duteil J, Rambert FA, Pessonnier J, Hermant J-F, Gomberg R, Assous E (1990) Central a-1 adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals. Eur J Pharmacol 180:49–58CrossRefPubMedGoogle Scholar
  7. Feeney DM, Sutton RL (1987) Pharmacotherapy for recovery of function after brain injury. Crit Rev Neurobiol 3:135–197PubMedGoogle Scholar
  8. Hadjiconstantinou M, Rossetti ZL, Paxton RC, Neff NH (1986) Administration of GM1 ganglioside restores the dopamine content in striatum after chronic treatment with MPTP. Neuropharmacology 9:1075–1077Google Scholar
  9. Hadjiconstantinou M, Neff NH (1988) Treatment with GM1 ganglioside restores striatal dopamine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse. J Neurochem 51:1190–1196PubMedGoogle Scholar
  10. Hadjiconstantinou M, Mariani AP, Neff NH (1989) GM1 ganglioside-induced recovery of nigrostriatal dopaminergic neurons after MPTP: an immunohistochemical study. Brain Res 484:297–303CrossRefPubMedGoogle Scholar
  11. Heikkila RE, Hess A, Duvoisin RC (1984) Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Science 224:1451–1453Google Scholar
  12. Hollander M, Wolfe DA (1973) Nonparametric statistical methods. Wiley, New YorkGoogle Scholar
  13. Hurd YL, Ungerstedt U (1989) Ca2+ dependence of the amphetamine, nomifensine, and Lu 19-005 effect on in vivo dopamine transmission. Eur J Pharmacol 166:261–269PubMedGoogle Scholar
  14. Janson AM, Agnati LF, Fuxe K, Cintra A, Sundström E, Zini I, Toffano G, Goldstein M (1988a) GM1 ganglioside protects against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of nigrostriatal dopamine neurons in the black mouse. Acta Physiol Scand 132:587–588PubMedGoogle Scholar
  15. Janson AM, Fuxe K, Agnati LF, Kitayama I, Härfstrand Anderson K, Goldstein M (1988b) 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 455:332–345CrossRefPubMedGoogle Scholar
  16. Janson AM, Fuxe K, Agnati LF, Toffano G, Goldstein M (1990) The ganglioside GM1 protects against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of nigral dopamine cells in the male C57BL/6 mouse. Soc Neurosci Abst 16 (2):413–415Google Scholar
  17. Javich JA, D'Amato RJ, Strittmatter SM, Snyder SN (1985) Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 82:2173–2177PubMedGoogle Scholar
  18. 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 19:995–1004PubMedGoogle Scholar
  19. Kuriyama T, Taguchi J-I, Kuriyama K (1990) Functional alterations in striatal cholinergic and striato-nigral GABAergic neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. Neurochem Int 16:319–329CrossRefGoogle Scholar
  20. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980Google Scholar
  21. Langston JW, Forno LS, Rebert CS, Irwin I (1984) Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the squirrel monkey. Brain Res 292:390–394CrossRefPubMedGoogle Scholar
  22. Luthman J (1989) Neonatal dopamine lesions: morphological, biochemical and behavioural characterization, Thesis, Karolinska Institutet, StockholmGoogle Scholar
  23. 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
  24. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, New YorkGoogle Scholar
  25. Ruggeri M, Ungerstedt U, Agnati LF, Mutt V, Härfstrand A, Fuxe K (1987) Effects of cholecystokinin peptides and neurotensin on dopamine release and metabolism in the rostral and caudal part of the nucleus accumbens using intracerebral dialysis in the anaesthetized rat. Neurochem Int 10:509–520CrossRefGoogle Scholar
  26. Sidman RL, Angevine JB, Taber Pierce E (1971) Atlas of the Mouse Brain and Spinal Cord, Harvard Univ Press, Cambridge MAGoogle Scholar
  27. Snedecor GW, Cochran WG (1980) Statistical methods, 7th edn, Iowa State University Press, Ames, IowaGoogle Scholar
  28. Sterio DC (1984) The unbiased estimation of number and sizes of arbitrary particles using the disector. J Microsc 134:127–136PubMedGoogle Scholar
  29. Sundström E, Jonsson G (1985) Pharmacological interference with the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse. Eur J Pharmacol 110:293–299PubMedGoogle Scholar
  30. Sundström E, Jonsson G (1986) Differential time course of protection by monoamine oxidase inhibition and uptake inhibition against MPTP neurotoxicity on central catecholamine neurons in mice. Eur J Pharmacol 122:275–278PubMedGoogle Scholar
  31. Sundström E, Strömberg I, Tsutsumi T, Olson L, Jonsson G (1987) Studies on the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57 BL/6 mice. Comparison with three other strains of mice. Brain Res 405:26–38CrossRefPubMedGoogle Scholar
  32. Tanganelli S, von Euler G, Fuxe K, Agnati LF, Ungerstedt U (1989) Neurotensin conteracts apomorphine-induced inhibition of dopamine release as studied by microdialysis in rat neostriatum. Brain Res 502:319–324PubMedGoogle Scholar
  33. Tanganelli S, Fuxe K, Ferraro L, Janson AM, Bianchi C (1991) Effects of the psychoactive drug Modafinil on acetylcholine and g-aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea-pig. Novel aspects on its mechanism of action. Naunyn-Schmiedeberg's Arch Pharmacol, submittedGoogle Scholar
  34. 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 1992

Authors and Affiliations

  • K. Fuxe
    • 1
  • A. M. Janson
    • 1
  • L. Rosén
    • 1
  • U. -B. Finnman
    • 1
  • S. Tanganelli
    • 2
  • M. Morari
    • 1
  • M. Goldstein
    • 3
  • L. F. Agnati
    • 4
  1. 1.Department of Histology and NeurobiologyKarolinska InstituteStockholmSweden
  2. 2.Department of PharmacologyUniversity of FerraraFerraraItaly
  3. 3.Department of PsychiatryNew York University Medical CenterNew YorkUSA
  4. 4.Department of Human PhysiologyUniversity of ModenaModenaItaly

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