Vol. 288, Issue 3, 1334-1339, March 1999

Age-Related Reductions in [³H]WIN 35,428 Binding to the Dopamine Transporter in Nigrostriatal and Mesolimbic Brain Regions of the Fischer 344 Rat¹

Meleik A. Hebert , Gaynor A. Larson , Nancy R. Zahniser and Greg A. Gerhardt

Neuroscience Training Program (M.A.H., N.R.Z., G.A.G.), Departments of Psychiatry (G.A.G.) and Pharmacology (N.R.Z., G.A.L., G.A.G.), and the Rocky Mountain Center for Sensor Technology (M.A.H., G.A.L., N.R.Z., G.A.G.), University of Colorado Health Sciences Center, Denver, Colorado

In the present study, we used the potent cocaine analog [³H]WIN 35,428 to map and quantify binding to the dopamine transporter (DAT) within the dorsal striatum, nucleus accumbens, substantia nigra, and ventral tegmental area in young (6-month-old), middle-aged (12-month-old), and aged (18- and 24-month-old) Fischer 344 rats. Quantitative autoradiographic analysis of indirect [³H]WIN 35,428 saturation curves revealed two-site binding for all four brain regions in every age group. The percentage of binding to the high- or low-affinity sites did not differ with age or region and was approximately 50%. However, significant age-related decreases in the overall density (B_max) of [³H]WIN 35,428-binding sites were observed in the striatum, nucleus accumbens, substantia nigra, and ventral tegmental area. The B_max within all brain regions declined by more than 15% every 6 months, with the B_max in the aged (24-month-old) group being approximately half that measured in the young adult (6-month-old) group. Competition experiments indicated that nomifensine also exhibited two-site binding to the DAT in Fischer 344 rats. No consistent age-related differences in binding affinities were noted with either [³H]WIN 35,428 or nomifensine. Taken together, these results support the hypothesis that functional DATs within the nigrostriatal and mesolimbic systems are down-regulated with age, without changing their affinity for ligands.