Age-related changes in nigrostriatal dopaminergic function in heterozygous mutant dopamine transporter knock-out mice.

In this report we compared three different parameters of nigrostriatal dopaminergic (NSDA) function - locomotor activity, striatal dopamine (DA) levels and 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratios between heterozygous mutant dopamine transporter mice (+/- DAT) and their wild type controls (+/+ DAT) at three different age range periods: 4-10, 11-17 and 18-24 months of age. Locomotor activity of the +/- DAT mice failed to differ over the three age periods sampled. In +/+ DAT mice a significant decrease in locomotor activity was obtained at the 18-24-month old period compared with scores at the two earlier age periods. In addition, locomotor scores of +/+ DAT mice at 18-24 months of age were significantly decreased as compared with scores of the +/- DAT mice at this age. Striatal DA concentrations of +/- DAT mice also failed to differ over the three age periods sampled, while that of +/+ DAT mice showed significant decreases in striatal DA at 11-17 and 18-24 months of age as compared to their 4-10-month old cohorts. Striatal DOPAC/DA ratios were significantly increased in both +/+ and +/- DAT mice at the 11-17 and 18-24 month age periods as compared with their respective 4-10-month old groups. Striatal DOPAC/DA ratios of +/- DAT mice were significantly greater than that of the +/+ DAT mice at 18-24 months of age. These findings reveal the significance of interactions between a mutation of the dopamine transporter and aging upon NSDA function and the importance of isolating such variables when using knock-out models.