Enhanced dopamine transporter activity in middle-aged Gdnf heterozygous mice

Glial cell line-derived neurotrophic factor (GDNF) supports the viability of midbrain dopamine (DA) neurons that degenerate in Parkinson's disease. Middle-aged, 12 month old, Gdnf heterozygous (Gdnf^+/-) mice have diminished spontaneous locomotor activity and enhanced synaptosomal DA uptake compared with wild type mice. In this study, dopamine transporter (DAT) function in middle-aged, 12 month old Gdnf^+/- mice was more thoroughly investigated using in vivo electrochemistry. Gdnf^+/- mice injected with the DAT inhibitor, nomifensine, exhibited significantly more locomotor activity than wild type mice. In vivo electrochemistry with carbon fiber microelectrodes demonstrated enhanced clearance of DA in the striatum of Gdnf^+/- mice, suggesting greater surface expression of DAT than in wild type littermates. Additionally, 12 month old Gdnf^+/- mice expressed greater D₂ receptor mRNA and protein in the striatum than wild type mice. Neurochemical analyses of striatal tissue samples indicated significant reductions in DA and a faster DA metabolic rate in Gdnf^+/- mice than in wild type mice. Altogether, these data support an important role for GDNF in the regulation of uptake, synthesis, and metabolism of DA during aging.