Age-Related Changes in the Capacity , Rate , and Modulation of Dopamine Uptake within the Striatum and Nucleus Accumbens of Fischer 344 Rats : An In Vivo Electrochemical Study 1

Age-related changes in the capacity, rate, and modulation of dopamine (DA) uptake within the striatum and the nucleus accumbens core of Fischer 344 rats were investigated using in vivo electrochemical recordings coupled with local drug application techniques. Equimolar amounts of DA were pressure ejected into the striatum and the nucleus accumbens of 6-, 12-, 18-, and 24-month old rats. The DA ejections produced larger DA signal amplitudes in the older rats, suggesting age-related differences in the capacity to clear extracellular DA. Within the striatum, the capacity and rate of DA uptake were reduced by 50% in the aged groups (18 and 24months) compared with the younger rats (6 and 12 months). In the nucleus accumbens, significant reductions in DA uptake capacity and rate were observed in the 24-month group. In both brain regions and in all age groups studied, the rate of DA uptake was found to be concentration-dependent until a maximal rate was reached. The maximum rate of DA transport was significantly reduced in both the striatum and the nucleus accumbens of aged rats (18 and 24 months versus 6 and 12 months). The ability of nomifensine, an inhibitor of the DA transporter, to modulate DA signal amplitudes in the striatum and the nucleus accumbens was also decreased with age (24 months versus 6 months). Taken together, these findings demonstrate substantial agerelated deficits in DA uptake processes within the striatum and the nucleus accumbens, consistent with the hypothesis that DA uptake may be slowed in aged animals to compensate for reductions in DA release. The progressive development of motor and cognitive dysfunction during senescence may be associated with alterations in neurotransmitter function in the central nervous system. In particular, age-related diminutions in dopamine (DA) neurotransmission within the basal ganglia of humans and animals are believed to contribute to changes in the execution and coordination of voluntary movements (Finch et al., 1981). Age-related alterations in both preand postsynaptic indices involved in dopaminergic (DAergic) neurotransmission have been well documented (Joseph et al. 1978; Goldman-Rakic and Brown, 1981; Rose et al. 1986; Friedemann and Gerhardt, 1992; Hebert and Gerhardt, 1998). The major regulator of DAergic neurotransmission is the reuptake of released DA via the dopamine transporter (DAT) (Giros et al., 1996). This high-affinity uptake process is sodium-, chloride-, and temperature-dependent; it is also saturable and has an affinity for monoamine substrates of approximately 0.1 to 2 mM (Meiergerd and Schenk, 1994; Lenhard et al. 1998). Not surprisingly, this important regulatory mechanism has also been shown to be altered with age. Several studies have shown a progressive age-related decline in the number of DA transporters (Zelnik et al., 1986) and a sharp decline in DAT mRNA in both rats and humans (Bannon and Whitty, 1997). As the status of this integral membrane protein during aging may have important implications for the proper functioning of the DAergic system, the actual dynamic performance of the DA uptake mechanism is of vital importance, because it regulates the amount of DA available for neurotransmission. It has been shown that the affinity of ligand binding to the rat and human DA transporter decreases with age (Shimizu and Prasad, 1991; Volkow et al., 1994). In addition, previous studies from our laboratory involving measures of stimulus-evoked release of DA in aged animals have yielded data implicating age-related changes in DAT function (Friedemann and Gerhardt, 1992; Hebert and Received for publication July 10, 1998 1 This work was supported by grants from U.S. Public Health Services Grants NS09199 and AG06434 and National Institutes of Health Training Grant HDO7408-02. In addition, this work was supported, in part, by a Level II Research Scientist Development Award (MH01245) from the National Institutes of Mental Health to G. Gerhardt. ABBREVIATIONS: DA; dopamine; DAergic, dopaminergic; DAT, dopamine transporter; F344, Fischer 344; NET, norepinephrine transporter; SERT, serotonin transporter; DOPAC, 3,4-dihydroxyphenylacetic acid; Tc, clearance rate; T20, time for signal amplitude to decay by 20%; T60, time for signal amplitude to decay by 60%; ANOVA, analysis of variance. 0022-3565/99/2882-0879$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 288, No. 2 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 288:879–887, 1999 879 at A PE T Jornals on Sptem er 6, 2017 jpet.asjournals. org D ow nladed from Gerhardt, 1998). The purpose of this study was to systematically study changes in DAT function that may occur with