Hypoxia during early developmental period induces long-term changes in thedopamine content and release in a mesencephalic cell culture

The present study was conducted to elucidate the long-term effects of expos ure to hypoxia of dopaminergic neurons during the early developmental perio d. Primary mesencephalic cell cultures prepared from fetal rats and contain ing 0.5-2% of dopaminergic neurons were exposed to hypoxia between in vitro days 1 and 6, the putative critical developmental period. Changes in the c ontent, release and uptake of dopamine were found to depend on the degree o f hypoxia and on the duration of exposure. Following moderate hypoxia (7 h, 5% O-2) on two consecutive days between in vitro days 1 and 3, the culture s showed a small increase in the dopamine levels, by 16%. After severe hypo xia (0% O-2/95% N-2 for 24 h), during the same time window, the cellular do pamine content was elevated by 100%. Moreover, severe hypoxia produced long -lasting modulations of the dopaminergic system. On in vitro day 14, cells exhibited increased levels of 3,4-dihydroxyphenylacetic acid and homovanill ic acid (by 34% and 55%, respectively), and elevations of both the spontane ous and potassium-stimulated dopamine release by 70%. The dopamine transpor t and metabolism of cells exposed to hypoxia between in vitro days 4 and 6 remained unchanged with regard to long-term effects. The present study provides strong evidence for the induction of long-arm ch anges in dopaminergic cells due to hypoxia during the critical developmenta l period in mesencephalic culture. The developmental period capable of indu cing long-lasting changes in dopamine metabolism is restricted to in vitro days 1-3. (C) 1999 IBRO. Published by Elsevier Science Ltd.