Oestrogen regulates the expression and function of dopamine transporters in astrocytes of the nigrostriatal system

Dopamine is actively and specifically eliminated from the extracellular space by astrocytes and neurones through dopamine transporters (DAT) and, afterwards, either recycled into vesicles or metabolised. The availability of dopamine reflects a critical point in the regulation of dopamine activity within the nigrostriatal circuit under normal and pathological conditions. From previous studies, we know that oestrogen regulates the efficacy of dopaminergic neurones at the synaptic level and improves dopamine function during Parkinson's disease. Accordingly, we investigated the contribution of local astroglial for extracellular dopamine elimination and the impact of oestrogen on DAT expression and activity. Using neonatal striatal and midbrain astrocyte cultures, we could demonstrate that astrocytes possess a specific dopamine uptake machinery and express DAT at considerable levels. The application of 17 beta-oestradiol decreased the expression of DAT by 80% and 60% in midbrain and striatal astroglia cultures, respectively. The unspecific dopamine transporters (OCT3, VMAT2) were not detected in astroglia. Functionally, oestrogen exposure inhibited the clearance of dopamine from the extracellular space by 45% and 35% compared to controls in midbrain and striatal astroglia, respectively. The effect on DAT expression and activity was completely antagonised by the oestrogen receptor antagonist ICI 182 780. In conclusion, our data suggest that the positive reinforcement of dopamine transmission under physiological conditions and the alleviative impact of oestrogen under pathological conditions may be the result of a decline in DAT expression and therefore delayed dopamine uptake by astroglia.