REGIONAL EFFECTS OF AGING ON DOPAMINERGIC FUNCTION IN THE FISCHER-344 RAT

To examine the consequences of aging on nigrostriatal (A9) and mesolimbic (A10) dopamine (DA) function, neurochemical and behavioral measurements were performed in male Fischer-344 rats 6, 12, 18, 24, and 30 months old. Regional analyses of dopaminergic overflow and uptake processes were examined using high-speed (5 Hz) in vivo electrochemical recordings and local drug application techniques. When potassium was used to elicit the presynaptic overflow of dopamine (DA) in striatal areas predominantly innervated by the substantia nigra, the amplitude of DA overflow was significantly lower in 24- and 30-month-old rats (p < 0.05 and p < 0.01 vs. 6 months, respectively). Furthermore, in ventral striatum (including the nucleus accumbens) which is innervated primarily by A10 DA cell bodies, potassium-evoked DA overflow release amplitudes were significantly lower in the 18, 24, and 30 month groups (p < 0.01 vs. 6 months). In addition, age-related differences between the dorsal and ventral striatum were found in a preliminary investigation of DA diffusion and clearance. Local application of nomifensine, a DA uptake inhibitor, significantly increased (p < 0.05 vs. control) the amplitude of the signal recorded after local application of 25-30 pmol DA in the ventral striatum of 6 month-old but not 24-month-old rats. High-performance liquid chromatography coupled with electrochemical detection (HPLC-EC) was used to analyze whole striatal DA levels, DA metabolite levels and turnover indices. However, no age-related differences in any of these variables were observed. Finally, a rod walking test was used to measure motor coordination and balance in animals prior to in vivo electrochemical recording. Rats in the 24- and 30-month-old age groups were found to be impaired in this task. In summary, this study identified regional age-dependent changes in presynaptic DA overflow and uptake.