Summary
The expression of proenkephalin (PENK), prodynorphin (PDYN) and c-fos genes was studied in the striatum of C57B1/6 mice treated with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP), which are used as a rodent model of Parkinson's disease (PD). Two weeks after systemic administration of MPTP (2×40 mg/kg, s.c. 18h apart), the lesion of the substantia nigra (SN) could be visualised by loss of the nigral tyrosine hydroxylase (TH) mRNA hybridization signal and by a 91% decrease in striatal dopamine levels. The levels of PENK and PDYN mRNAs were not significantly changed in the striatum of the lesioned mice, as compared to non-treated controls. The induction of the immediate early gene c-fos by the dopamine D2 receptor antagonist haloperidol was not altered, while the selective D1 receptor agonist SKF 38393 failed to induce c-fos in the striatum of MPTP-treated mice.
These results are in contrast to the data concerning rats with the 6-hydroxydopamine (6-OHDA) lesion of the SN, which serve as another rodent model of PD. In the striata of 6-OHDA-lesioned rats, PENK gene is upregulated, PDYN gene is down-regulated and the induction of c-fos gene by D2 receptor antagonists is abolished, whereas selective D1 receptor agonists induce c-fos gene, which does not occur in non-lesioned rats.
We presume that the lack of influence of the MPTP lesion in mice on the striatal gene expression was mainly caused by insufficient dopamine depletion in the striatum, which could not be increased in this model. The importance of the changes observed in 6-OHDA-lesioned rats has been discussed in the context of the mouse and primate MPTP models of PD.
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References
Angulo JA, Davis LG, Burkhart BA, Christoph GR (1986) Reduction of the striatal dopaminergic neurotransmission elevates striatal proenkephalin mRNA. Eur J Pharmacol 130: 341–343
Augood SJ, Emson PC, Mitchell IJ, Boyce S, Clarke CE, Crossman AR (1989) Cellular localisation of enkephalin gene expression in MPTP-treated cynomolgus monkeys. Mol Brain Res 6: 85–92
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: 4546–4550
Cadet JL, Zhu SM, Angulo JA (1992) Quantitative in situ hydridization evidence for differential regulation of proenkephalin and D2 dopamine receptor mRNA levels in the rat striatum: effects of unilateral intrastriatal injections of 6-hydroxydopamine. Mol Brain Res 12: 59–67
Chomczyński P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159
Civelli O, Douglass J, Goldstein A, Herbert E (1985) Sequence and expression of the rat prodynorphin gene. Proc Natl Acad Sci USA 82: 491–429
Dacko S, Schneider JS (1991) Met-enkephalin immunoreactivity in the basal ganglia in symptomatic and asymptomatic MPTP-exposed monkeys: correlation with degree of parkinsonian symptoms. Neurosci Lett 127: 49–52
Dragunow M, Robertson GS, Faull RLM, Robertson HA, Jansen K (1990) D2 dopamine receptor antagonists induce Fos and related proteins in rat striatal neurons. Neuroscience 37: 287–294
Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ Jr, Sibley DR (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250: 1429–1432
Graybiel AM, Moratalla R, Robertson HA (1990) Amphetamine and cocaine induce drug-specific activation of the c-fos gene in the striosome-matrix compartments and limbic subdivisions of the striatum. Proc Natl Acad Sci USA 87: 6912–6916
Gudehithlu KP, Duchemin AM, Tejwani GA, Neff NH, Hadjiconstantinou M (1991) Preproenkephalin mRNA and methionine-enkephalin increase in mouse striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. J Neurochem 56: 1043–1048
Gupta M, Gupta BK, Thomas R, Bruemmer V, Sladek JR Jr, Felten DL (1986) Aged mice are more sensitive to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment than young adults. Neurosci Lett 79: 326–331
Hefti F, Melamed E, Wurtman RJ (1980) Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization. Brain Res 195: 123–137
Heikkila RE, Hess A, Duvoisin RC (1984) Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Science 224: 1451–1453
Hong JS, Yang HY, Fratta W, Costa E (1978) Rat striatal methionine-enkephalin content after chronic treatment with cataleptogenic and noncataleptogenic antischizophrenic drugs. J Pharmacol Exp Ther 205: 141–147
Höllt V, Haarmann I, Millan MJ, Herz A (1987) Prodynorphin gene expression is enhanced in the spinal cord of chronic arthritic rats. Neurosci Lett 73: 90–94
Ichikawa S, Sasaoka T, Nagatsu T (1991) Primary structure of mouse tyrosine hydroxylase deduced from its cDNA. Biochem Biophys Res Commun 176: 1610–1616
Jenner P, Taquet H, Mauborgne A, Banoliel J, Cesselin F, Rose S, Javoy-Agid F, Agid Y, Marsden SD (1986) Lack of change in basal ganglia neuropeptide content following subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of the common marmoset. J Neurochem 47: 1548–1551
Kupsch A, Löschmann P-A, Sauer H, Arnold G, Renner P, Pufal D, Burg M, Wachtel H, ten Bruggencate G, Oertel WH (1992) Do NMDA receptor antagonists protect against MPTP-toxicity? Biochemical and immunocytochemical analyses in black mice. Brain Res 592: 74–83
Langston JW, Forno LS, Reber 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: 390–394
Langston JW, Tetrud JW, Irwin I (1983) Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219: 979–980
Lavoie B, Parent A, Bedard PJ (1991) Effects of dopamine denervation on striatal peptide expression in parkinsonian monkeys. Can J Neurol Sci 19: 373–375
Lewis SA, Gwo-Shu Lee M, Cowan NJ (1985) Five mouse tubulin isotypes and their regulated expression during development. J Cell Biol 101: 852–861
Li SJ, Jiang HK, Stachowiak MS, Hudson PM, Owyang V, Nanry K, Tilson HA, Hong JS (1990) Influence of nigrostriatal dopaminergic tone on the biosynthesis of dynorphin and enkephalin in rat striatum. Mol Brain Res 8: 219–225
Mitsuo K, Cosi C, Harvey-White JD, Schwartz JP (1993) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) effects on enkephalinergic neurons in various regions of mouse brain. Neurochem Int 22: 175–182
Morris BJ, Herz A, Höllt V (1989) Localization of striatal opioid gene expression and its modulation by mesostriatal dopamine pathway: an in situ hybridization study. J Mol Neurosci 1: 9–18
Morris BJ, Höllt V, Herz A (1988) Dopaminergic regulation of striatal proenkephalin mRNA and prodynorphin mRNA: contrasting effects of D1 and D2 pathways of pain: Fos/Jun-mediated activation of noncanonical AP-1 site in the prodynorphin gene. Neuron 6: 607–617
Naranjo JR, Mellstrom B, Achaval M, Sassone-Corsi P (1991) Molecular pathways of pain: Fos/Jun-mediated activation of a noncanonical AP-1 site in the produnorphin gene. Neuron 6(4): 607–617
Nguyen TV, Kosofsky BE, Birnbaum R, Cohen BM, Hyman SE (1992) Differential expression of c-Fos and Zif268 in rat striatum after haloperidol, clozapine, and amphetamine. Proc Natl Acad Sci USA 89: 4270–4274
Normand E, Popovici T, Onteniente B, Fellmann D, Piatier-Tonneau D, Auffray C, Bloch B (1988) Dopaminergic neurons of the substantia nigra modulate preproenkephalin A gene expression in rat striatal neurons. Brain Res 439: 39–48
Perez-Otano I, Herrero MT, Luquin MR, Obeso JA, Del-Rio J (1992) Chronic MPTP treatment reduces substance P and met-enkephalin content in the basal ganglia of the marmoset. Brain Res 585: 156–160
Pollack AE, Wooten GF (1992) Differential regulation of striatal preproenkephalin mRNA by D1 and D2 dopamine receptors. Mol Brain Res 12: 111–119
Probst A, Mengod G, Palacios JM (1991) Neurotransmitter receptors in human brain diseases. Curr Top Pathol 83: 219–270
Reimer S, Höllt V (1991) GABAergic regulation of striatal opioid gene expression. Mol Brain Res 10: 49–54
Reimer S, Sirinathsinghji DJS, Nikolarakis KE, Höllt V (1992) Differential dopaminergic regulation of proenkephalin and prodynorphin mRNAs in the basal ganglia of rats. Mol Brain Res 12: 259–266
Ricaurte GA, Irwin I, Forno LS, DeLanney LE, Langston E, Langston JW (1987) Aging and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of dopaminergic neurons in the substantia nigra. Brain Res 403: 43–51
Robertson GS, Fibiger HC (1992) Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. Neuroscience 46: 315–328
Robertson GS, Herrera DC, Dragunow M, Robertson HA (1989) L-Dopa activates c-fos in the striatum ipsilateral to a 6-hydroxydopamine lesion of the substantia nigra. Eur J Pharmacol 159: 99–100
Robertson GS, Vincent SR, Fibiger HC (1990) Striatonigral projection neurons contain D1 dopamine receptor-activated c-fos. Brain Res 523: 228–290
Robertson HA, Peterson MR, Murphy K, Robertson GS (1989) D1-dopamine receptor agonists selectively activate striatal c-fos independent of rotational behaviour. Brain Res 503: 346–349
Sabol SL, Yoshikawa K, Hong JS (1983) Regulation of methionine enkephalin precursor messenger RNA in rat striatum by haloperidol and lithium. Biochem Biophys Res Commum 113: 391–399
Schäfer MK-J, Hermann JP, Watson SJ (1993) In situ hybridization histochemistry. In: London ED (ed) Imaging drug action in the brain, 1st edn. CRC Press, Boca Raton, pp 337–378
Sirinathsinghji DJS, Dunnett SB (1991) Increased proenkephalin mRNA levels in the rat neostriatum following lesion of the ipsilateral nigrostriatal dopamine pathway with 1-methyl-4-phenylpyridinium ion (MPP+): reversal by embryonic nigral dopamine grafts. Mol Brain Res 9: 263–269
Sivam SP (1991) Dopamine dependent decrease in enkephalin and substance P levels in basal ganglia regions of postmortem parkinsonia brains. Neuropeptides 18: 201–207
Sonnenberg JL, Rauscher FJ, Morgan JI, Curran T (1989) Regulation of proenkephalin by Fos and Jun. Science 246: 1622–1625
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 C57BL/6 mice. Comparison with three other strains of mice. Brain Res 405: 26–38
Tang F, Costa E, Schwartz JP (1983) Increase of proenkephalin mRNA and enkephalin content of rat striatum after daily injection of haloperidol for 2 to 3 weeks. Proc Natl Acad Sci USA 80: 3841–3844
Taquet H, Javoy-Agid F, Hamon M, Legrand JC, Agid Y, Cesselin F (1983) Parkinson's disease affects differentially Met5- and Leu5-enkephalin in the human brain. Brain Res 280: 379–382
Taquet H, Nomoto M, Rose S, Jenner P, Javoy-Agid F, Mauborgne A, Benoliel JJ, Marsden C, Legrand JC, Agid Y, et al (1988) Levels of Met-enkephalin, Leu-enkephalin, substance P and cholecystokinin in the brain of the common marmoset following long term 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. Neuropeptides 12: 105–110
Taylor MD, de Ceballos ML, Rose S, Chang PN, Jenner P, Marsden CD (1991) Neuropeptides levels in the basal ganglia of aged common marmosets following prolonged treatment with MPTP. J Neural Transm [PD Sect] 3: 99–108
Thal LJ, Sharpless NS, Hirschhorn ID, Horowitz SG, Makman MH (1983) Striatal met-enkephalin concentration increases following nigrostriatal denervation. Biochem Pharmacol 32: 3297–3301
Trujillo KA, Day R, Akil H (1990) Regulation of striatonigral prodynorphin peptides by dopaminergic agents. Brain Res 518: 244–256
Van Beveren C, van Straaten F, Curran T, Müller R, Verma IM (1983) Analysis of FBJ-MuSV provirus and c-fos (mouse) gene reveals that viral and cellular fos gene products have different carboxy termini. Cell 32: 1241–1255
Wallace RA, Boldry R, Schmittgen T, Miller D, Uretsky N (1984) Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on monoamine neurotransmitters in mouse brain and heart. Life Sci 35: 285–291
Waters CM, Peck R, Rossor M, Reynolds GP, Hunt SP (1988) Immunocytochemical studies on the basal ganglia and substantia nigra in Parkinson's disease and Huntington's chorea. Neuroscience 25: 419–438
Yoshikawa K, Williams C, Sabol SL (1984) Rat brain proenkephalin mRNA—cDNA cloning, primary structure, and distribution in the central nervous system. J Biol Chem 259: 14301–14308
Young WS III, Bonner TI, Brann MR (1986) Mesencephalic dopamine neurons regulate the expression of neuropeptide mRNAs in the rat forebrain. Proc Natl Acad Sci USA 83: 9827–9831
Zamir N, Skofitsch G, Bannon MJ, Helke CJ, Kopin IJ, Jacobowitz DM (1984) Primate model of Parkinson's disease: alterations in multiple opioid systems in the basal ganglia. Brain Res 322: 356–360
Zigmond MJ, Abercrombie ED, Berger TW, Grace AA, Stricker EM (1990) Compensations after lesions of central dopaminergic neurons: some clinical and basic implications. Trends Neurosci 13: 290–296
Ziółkowska B, Höllt V (1993) MK-801 markedly reduces the induction of c-fos gene by haloperidol in the mouse striatum. Neurosci Lett 156: 39–42
Zuddas A, Corsini GU, Shinelli S, Johannesen JN, di Porzio U, Kopin I (1989) MPTP treatment combined with ethanol or acetaldehyde selectively destroys dopaminergic neurons in mouse substantia nigra. Brain Res 501: 1–10
Zurawski G, Benedik M, Kamb BJ, Abrams JS, Zurawski S, Lee FD (1986) Activation of mouse T-helper cells induces abundant preproenkephallin mRNA synthesis. Science 232: 772–775
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Ziolkowska, B., Horn, G., Kupsch, A. et al. The expression of proenkephalin and prodynorphin genes and the induction of c-fos gene by dopaminergic drugs are not altered in the striatum of MPTP-treated mice. J Neural Transm Gen Sect 9, 151–164 (1995). https://doi.org/10.1007/BF02259657
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DOI: https://doi.org/10.1007/BF02259657