Fetal exposure to methamphetamine in utero stimulates development of serotonergic neurons in three-dimensional reaggregate tissue culture.

Methamphetamine is a potent psychomotor stimulant with neurotoxic potential which is widely abused by females of childbearing age, raising serious public health concerns in terms of exposure of the fetus to the drug. The current study was conducted to determine the effect of maternal administration of methamphetamine on developing monoaminergic neurons using three-dimensional reaggregate tissue cultures prepared from fetal mesencephalic and striatal cells. In this culture system, the dopaminergic and serotonergic mesencephalic-striatal projections are reconstructed and develop with a time course similar to that observed in vivo. Pregnant C57Bl/6J mice were injected twice daily with 40 mg/kg methamphetamine or saline from gestational days 6-13. On gestational day 14, cells from methamphetamine and saline-exposed embryos were used to prepare reaggregate cultures. Levels of neurotransmitters and their metabolites in the reaggregates and culture medium were monitored at 14, 29, 43, and 64 days of culture. Reaggregates prepared from methamphetamine-exposed embryos showed a significant elevation in serotonin levels at all culture ages compared to reaggregates prepared from saline-treated embryos. Levels of 5-HIAA in reaggregates and culture medium were also elevated in 14- and 29-day-old cultures derived from drug-exposed embryos. The development of the dopaminergic nigrostriatal projection was resistant to repeated in utero exposure to methamphetamine. In contrast, exposure of the fetus to methamphetamine, during early to midgestation, produced a long-lasting stimulatory effect on serotonergic development in culture.