Effects of perinatal asphyxia on the mesostriatal/mesolimbic dopamine system of neonatal and 4-week-old male rats.

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 degrees 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. DO-PAC 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.