Summary
Microdialysis was used to study the biotransformation of l-DOPA in the striatum and substantia nigra of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra. The animals were pretreated with carbidopa (50 mg/kg p.o.) for 5 days. They were anaesthetized, and microdialysis probes were implanted into the intact and denervated striatum and into the intact and lesioned substantia nigra. The biotransformation of l-DOPA (5 mg/kg i.p.) in these regions was investigated. These results were compared with those obtained after administration of a much higher dose of l-DOPA (100 mg/kg i.p.). Changes in extracellular l-DOPA, 3-O-methyldopa (3-OMD), dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by HPLC with electrochemical detection.
Although rats with a unilateral nigrostriatal lesion did not show rotational behaviour after 5 mg/kg l-DOPA, DA levels were increased significantly both in the intact and the denervated striatum and in the intact and the lesioned substantia nigra. This increase was most pronounced in the denervated striatum. At 100 mg/kg l-DOPA, the increases in extracellular dopamine in intact and denervated striatum were about twice as high as the increases observed at the lower dose. A similar increase was observed in the intact substantia nigra. However, in the lesioned substantia nigra there was a fourfold increase. l-DOPA, at both doses, was evenly distributed between the brain areas studied and the lesion had no effect on the uptake of the drug at the blood-brain barrier.
Our data suggest that l-DOPA in the substantia nigra might play a role additional to that in the striatum in relieving symptoms of Parkinson's disease. Even at a low dose (5 mg/kg i.p.), the drug had an effect on extracellular dopamine in all the brain regions studied.
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References
Abercrombie ED, Bonatz AE, Zigmond MJ (1990) Effects of l-DOPA on extracellular dopamine in striatum of normal and 6-hydroxydopamine-treated rats. Brain Res 525:36–44
Aiso M, Shigematsu K, Kebabian JW, Potter WZ, Cruciani RA, Saavedra JM (1987) Dopamine D 1 receptor in rat brain: a quantitative autoradiographic study with 1251-SCH 23982. Brain Res 408:281–285
Barbeau A (1969) l-DOPA therapy in Parkinson's disease: a critical review of nine years' experience. Can Med Assoc J 101:59–68
Barbeau A (1981) The use of l-DOPA in Parkinson's disease: a 20-year follow-up. Trends Pharmacol Sci 2:297–299
Becker JB, Adams FA, Robinson TE (1988) Intraventricular microdialysis: a new method for determining monoamine metabolite concentrations in the cerebrospinal fluid of freely moving rats. J Neurosci Methods 24:259–269
Benveniste H (1989) Brain microdialysis: short review. J Neurochem 52:1667–1679
Benveniste H, Hüttemeier PC (1990) Microdialysis — theory and application. Prog Neurobiol 35:195–215
Bracha HS, Shults C, Glick SD, Kleinman JE (1987) Spontaneous asymmetric circling behaviour in hemi-parkinsonism: a human equivalent of the lesioned-circling rodent behaviour. Life Sci 40:1127–1130
Brannan T, Knott P, Kauffman H, Leung L, Yahr M (1989) Intracerebral dialysis monitoring of striatal dopamine release and metabolism in response to l-DOPA. J Neural Transm 75:149–157
Castenada E, Whishaw IQ, Robinson TE (1990) Changes in striatal dopamine neurotransmission following recovery from bilateral 6-OHDA lesion: variation as a function of lesion size. J Neurosci 10:1847–1854
Cheramy A, Leviel V, Glowinski J (1981) Dendritic release of dopamine in substantia nigra. Nature 289:537–542
Costall B, Kelly ME, Naylor RJ (1983) Does contralateral circling involve action of drugs on hyposensitive striatal dopamine receptors in the hemisphere contralateral to denervation? Neuropharmacology 22:295–302
Dawson TM, Gehlert DR, McCabe RT, Barnett A, Wamsley JK (1986) D 1 dopamine receptors in the rat brain: a quantitative autoradiographic analysis. J Neurosci 6:2352–2358
De Keyser J, Claeys A, De Backer JP, Ebinger G, Roels F, Vauquelin G (1988) Autoradiographic localization of D 1 and D 2 dopamine receptors in the human brain. Neurosci Lett 91:142–147
De Keyser J, Vauquelin G, Ebinger G (1991) D 1 and D 2 dopamine receptors in human sustantia nigra: localization and the effect of aging. J Neurochem 56:1130–1134
Dubois A, Savasta M, Curet O, Scatton B (1986) Autoradiographic distribution of the D 1 agonist [3 H]SKF 38393, in rat brain and spinal cord. Comparison with the distribution of D 2 dopamine receptors. Neuroscience 19:125–137
Geffen LB, Jessell TM, Cuello AC, Iverson LL (1976) Release of dopamine from dendrites in rat substantia nigra. Nature 260:258–260
Hornykiewicz O (1974) The mechanisms of action of l-DOPA in Parkinson's disease. Life Sci 15:1249–1259
Hornykiewicz O (1975) Parkinson's disease and its chemotherapy. Biochem Pharmacol 24:1061–1065
König JFR, Klippel RA (1963) The rat brain. A stereotaxic atlas. Williams & Wilkins, Baltimore
Nieoullon A, Cheramy A, Glowinski J (1978) Release of dopamine in both caudate nuclei and both substantia nigrae in response to unilateral stimulation of cerebellar nuclei in the cat. Brain Res 148:143–152
Nieoullon A, Cheramy A, Glowinski J (1977) Interdependence of the nigrostriatal dopaminergic systems on the two sides of the brain in the cat. Science 198:416–418
Nock B, Sedvail G, McEwen BS (1986) Quantitative autoradiography of [3 H]piquindone binding sites (dopamine D 2 receptors) in rat brain. Eur J Pharmacol 121:387–393
Pycock CJ (1980) Turning behaviour in animals. Neuroscience 5:461–514
Rinne UK, Sonninen V, Surtola T (1973) Acidoamine metabolites in cerebrospinal fluid of parkinsonian patients treated with levodopa alone or combined with a decarboxylase inhibitor. Eur Neurol 9:349–362
Robinson TE, Whishaw IQ (1988) Normalization of extracellular dopamine in striatum following recovery from a partial unilateral 6-OHDA lesion of the substantia nigra: a microdialysis study in freely moving rats. Brain Res 450:209–224
Touchet N, Bennett JP (1989) The metabolism of systemically-administered l-dihydroxyphenylalanine by brain microdialysis. Neuropharmacology 28:1217–1222
Ungerstedt U, Herrera-Marschitz M (1981) Behavioural pharmacology of dopamine receptor mechanisms. In: Stärne L, Hedqvist P, Lagercrantz H, Wennmalm A (eds) Chemical neurotransmission, 75 years. Academic Press, New York, pp 481–494
Wong SL, Wang YF, Sawchuk EJ (1992) Analysis of zidovudine distribution to specific regions in rabbit brain using microdialysis. Pharm Res (in press)
Werner W, Harrison W, Klawans H (1969) l-DOPA and cerebrospinal fluid homovanillic acid in parkinsonism. Life Sci 8:971–976
Westerink BHC, De Vries JB, Duran R (1990) Use of microdialysis for monitoring tyrosine hydroxylase activity in the brain of conscious rats. J Neurochem 54:381–387
Zetterström T, Herrera-Marschitz M, Ungerstedt U (1986) Simultaneous measurement of dopamine release and rotational behaviour in 6-hydroxydopamine denervated rats using intracerebral dialysis. Brain Res 376:1–7
Zigmond MJ, Abercrombie ED, Berger TW, Grace AA, Stricker EM (1990) Compensation after lesions of central dopaminergic neurons: Some clinical and basic implications. Trends Neurosci 7:290–295
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Sarre, S., Herregodts, P., Deleu, D. et al. Biotransformation of l-DOPA in striatum and substantia nigra of rats with a unilateral, nigrostriatal lesion: a microdialysis study. Naunyn-Schmiedeberg's Arch Pharmacol 346, 277–285 (1992). https://doi.org/10.1007/BF00173540
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DOI: https://doi.org/10.1007/BF00173540