Abstract
The present study was undertaken in order to study the effects of perinatal asphyxia on tyrosine hydroxylase (TH) activity, dopamine levels and turnover, and dopamine metabolites (3,4-dihydroxyphenylacetic acid, DOPAC, homovanillic acid, HVA, and 3-methoxytyramine, 3-MT, analyzed by high-performance liquid chromatography, HPLC) measured in the basal ganglia of the 20- to 40-min-old newborn and 4-week-old male rat. Asphyxia was induced in pups by placing the fetuses, still in their uterus horns removed by hysterectomy from pregnant rats at full term, in a 37°C water bath for 15–16 min or 19–20 min. Following asphyxia, the uterus horns were opened, and the pups were removed and stimulated to breathe. A 100% and 50–80% pup survival was obtained following 15–16 min and 19–20 min of asphyxia, respectively. Acute changes were studied in brains from newborn pups 20–40 min after delivery, and long-term changes were studied in brains from 4-week-old rats. No changes in TH-activity could be observed in the substantia nigra/ventral tegmental area (SN/VTA), the striatum, or the accumbens nucleus/olfactory tubercle (ACC/TUB), in the newborn or the 4-week-old rat. In the newborn rat, 19–20 min of asphyxia increased (as compared to controls) dopamine levels in the SN/VTA to 136±14% and in the ACC/TUB to 160±10%, indicating an increased synthesis and/or release of dopamine. DOPAC levels were increased in the SN/VTA to 150±14% and in the ACC/TUB to 151±10%, and HVA levels were increased to 152±16% in the striatum and to 117±4% in the ACC/TUB. Following 15–16 min of asphyxia, dopamine levels were increased to 130±12% in the ACC/TUB, and DOPAC levels were increased to 135±6% and 130±12% in the SN/VTA and the ACC/TUB, respectively. This suggests that the increased dopamine levels may preferably reflect an increased release of dopamine following perinatal asphyxia. In the 4-week-old rat, dopamine levels were decreased in the SN/VTA to 71±4%, in the striatum to 52±8%, and in the ACC/TUB to 53±7%, following 19–20 min of perinatal asphyxia as compared to controls. No changes were observed in DOPAC, HVA, or 3-MT levels, indicating that the reduced dopamine levels reflect a reduced dopamine synthesis following perinatal asphyxia. A decrease in dopamine utilization was observed in the striatum to 15±8% and in the ACC/TUB to 9±13% following 19–20 min of perinatal asphyxia as compared to controls. This indicates that perinatal asphyxia produced long-lasting reductions in activity in the mesostriatal/mesolimbic dopamine systems in the 4-week-old rat.
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References
Andén N-E, Corrodi H, Fuxe K (1969) Turnover studies using synthesis inhibition. In: Hooper G (ed) Metabolism of amines in the brain. Macmillan, London, pp 38–47
Andersson K, Bjelke B, Bolme P, Ögren SO (1992) Asphyxia-induced lesion of the rat hippocampus (CA1, CA3) and the nigro-striatal dopamine system. In: Gross J (ed) Hypoxia and ischemia. (CNS, vol 41) Wissenschafliche Publikationen der Humboldt-Universität zu Berlin, R. Medizin, pp 71–76
Andersson K, Blum M, Chen Y, Eneroth P, Gross J, Ungethüm U, Bjelke B, Bolme B, Diaz R, Herrera-Marschitz M, Jamieson L, Loidl F, Åström G, Ögren SO (1995) Perinatal asphyxia increase in bFGF mRNA levels and DA cell body number in the mesencephalon of rats. Neuroreport 6:375–378
Andersson K, Fuxe K, Agnati LF (1985) Determinations of catecholamine half-lives and turnover rates in discrete catecholamine nerve terminal systems of the hypothalamus, the preoptic region and the forebrain by quantitative histofluorimetry. Acta Physiol Scand 123:411–426
Bjelke B, Andersson K, Ögren SO, Bolme P (1991) Asphyxic lesion: proliferation of tyrosine hydroxylase-immunoreactive nerve cell bodies in the rat substantia nigra and functional changes in dopamine neurotransmission. Brain Res 543:1–9
Boksa P, Krishnamurthy A, Brooks W (1995) Effects of a period of asphyxia during birth on spatial learning in the rat. Pediatr Res 37:489–496
Chen Y, Ögren SO, Bjelke B, Bolme P, Eneroth P, Gross J, Loidl F, Herrera-Marschitz M, Andersson K (1995) Nicotine treatment counteracts perinatal asphyxia-induced changes in the meso-striatal/-limbic dopamine systems and in motor behaviour in the 4 week old male rat. Neuroscience 68:531–538
Coyle JT, Axelrod J (1972) Tyrosine hydroxylase in the rat brain: developmental characteristics. J Neurochem 19:1117–1123
Dahlström A, Fuxe K (1964) Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of the brain stem neurons. Acta Physiol Scand [Suppl 232] 62:1–55
Dell'Anna E, Chen Y, Loidl CF, Andersson K, Luthman J, Goiny M, Rawal R, Lindgren T, Herrera-Marschitz M (1995) Short-term effects of perinatal asphyxia studied with fos-immunocytochemistry and in vivo microdialysis in the rat. Exp Neurol 131:279–287
Dobbing J, Sands J (1979) Comparative aspects on the brain growth spurt. Early Hum Dev 3:79–83
Elverfors A, Nissbrandt H (1992) Effects of d-amphetamine on dopaminergic neurotransmission; a comparison between the substantia nigra and the striatum. Neuropharmacology 31:661–670
Herrera-Marschitz M, Loidl CF, Andersson K, Ungerstedt U (1993) Prevention of mortality induced by perinatal asphyxia: hypothermia or glutamate antagonism? Amino Acids 5: 413–419
Herrera-Marschitz M, Loidl F, You Z-B, Andersson K, Silveria R, O'Connor WT, Giony M (1994) Neurocircuitry of the basal ganglia studied by monitoring neurotransmitter release: effects of intracerebral and perinatal asphyctic lesions. Mol Neurobiol 9:171–182
Hill A (1991) Current concepts of hypoxic-ischemic cerebral injury in the term newborn. Pediatr Neurol 7:317–325
Hossman K-A (1991) Animal models of cerebral ischemia. Review of literature. Cerebrovasc Dis [Suppl 1] 1:2–15
Jonsson G, Hallman H, Mefford I, Adams RN (1980) The use of liquid chromatography with electrochemical detection for the determination of adrenaline and other biogenic monoamines in the CNS. In: Fuxe K, Goldstein M, Hökfelt B, Hökfelt H (eds) Central adrenaline neurons. Pergamon, Oxford, pp 59–71
Kalo T, Yamaguchi T, Togari A, Nagatsu T, Yajima T, Maeda N, Kumegawa M (1982) Ontogenesis of monoamine-synthesizing enzyme activities and biopterin levels in rat brain or salivary glands, and the effect of thyroxine administration. J Neurochem 38:896–901
Kostic VS, Przedborski S, Jackson-Lewis V, Cadet JL, Burke RE (1991) Effect of unilateral perinatal hypoxic-ischemic brain injury on striatal dopamine uptake sites and D1 and D2 receptors in adult rats. Neurosci Lett 129:197–200
Lewis SW, Murray RM (1987) Obstetric complications, neurodevelopmental deviance and risk of schizophrenia. J Psychiatr Res 21:413–421
Loidl CF, Herrera-Marschitz M, Andersson K, You Z-B, Goiny M, O'Connor WT, Silveira R, Rawal R, Bjelke B, Chen Y, Ungerstedt U (1994) Long-term effects of perinatal asphyxia on basal ganglia neurotransmitter systems studied with microdial ysis in rat. Neurosci Lett 175:9–12
Low JA (1993) Relationship of fetal asphyxia to neuropathology and deficits in children. Clin Invest Med 16:133–140
Lowry O, Rosenborough N, Farr C, Randall R (1951) Protein measurement with the Folin reagent. J Biol Chem 193:265–275
McKenzie JS, Kemm RE, Wilcock LN (1984) The basal ganglia. Structure and function. Adv Neurol 27
Nagasawa H, Araki T, Kogure K (1992) Alteration of dopamine D1 receptors in the strionigral system of the postischemic rat brain. Neurosci Lett 134:271–274
Nissbrandt H, Carlsson A (1987) Turnover of dopamine and dopamine metabolites in rat brain: comparison between striatum and substantia nigra. J Neurochem 49:959–967
Nissbrandt H, Sundström E, Jonsson G, Hjorth S, Carlsson A (1989) Synthesis and release of dopamine in rat brain: comparison between substantia nigra pars compacta, pars reticulata and striatum. J Neurochem 52:1170–1182
Okuno S, Fujisawa H (1983) Assay of tyrosine 3-mono-oxygenase using the coupled nonenzymatic decarboxylation of Dopa. Anal Biochem 129:405–411
Raju T (1992) Some animal models for the study of perinatal asphyxia. Biol Neonate 62:202–214
Reid M, Herrera-Marschitz M, Hökfelt T, Terenius L, Ungerstedt U (1988) Differential modulation of striatal dopamine release by intranigral injection of γ-aminobutyric acid (GABA), dynorphin A and substance P. Eur J Pharmacol 147:411–420
Romijn HJ, Hofman MA, Gramsbergen A (1991) At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby? Early Hum Dev 26:61–67
Shen R, Hamilton-Byrd EL, Vulliet PR, Kwan S-W, Creed W (1986) Abell: a simplified 14CO2-trapping microassay for tyrosine hydroxylase activity. J Neurosci Methods 16:163–173
Ungerstedt U (1980) Behavioural pharmacology reflecting catecholamine neurotransmission. In: Szekeres L (ed) Handbook of experimental pharmacology, vol 54/I. Springer, Berlin Heidelberg New York, pp 499–519
Venero JL, Machado A, Cano J (1991a) Age effects on monoamine turnover of the rat substantia nigra. Brain Res 557:109–114
Venero JL, Machado A, Cano J (1991b) Turnover of dopamine and serotonin and their metabolites in the striatum of aged rats. J Neurochem 56:1940–1948
Venero JL, Santiago M, Machado A, Cano J (1989) Determination of monoamines and both forms of monoamine oxidase in the rat's substantia nigra during postnatal development. Life Sci 45:1277–1283
Volpe JJ (1987) Neurology of the newborn, vol 22. Saunders, Philadelphia
Voorn P, Kalsbeek A, Jorritsma-Byham B, Groenewegen HJ (1988) The pre- and postnatal development of the dopaminergic cell groups in the ventral mesencephalon and the dopaminergic innervation of the rat. Neuroscience 25:857–887
Younkin DP (1992) Hypoxic-ischemic brain injury of the newborn-statement of the problem and overview. Brain Pathol 2:209–210
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Ungethüm, U., Chen, Y., Gross, J. et al. Effects of perinatal asphyxia on the mesostriatal/mesolimbic dopamine system of neonatal and 4-week-old male rats. Exp Brain Res 112, 403–410 (1996). https://doi.org/10.1007/BF00227946
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DOI: https://doi.org/10.1007/BF00227946