Extracellular glutamate levels increase with age in the lateral striatum: potential involvement of presynaptic D-2 receptors.

In the lateral striatum of aged rats, dopamine D-2 receptor density is reduced and glutamate tissue content is elevated. D-2 receptor agonists have been shown to inhibit stimulated glutamate release. In the present study, microdialysis was used to investigate a potential role for D-2 receptors in the modulation of striatal glutamate efflux from 4-, 12-, 18-, and 24-26-month-old Fischer 344 rats. Extracellular basal glutamate concentrations significantly increased as a function of age in the lateral, but not medial, striatum. Neither the D-2 agonist, LY 163502, nor the D-2 antagonist, sulpiride, influenced basal glutamate efflux, suggesting that the dopaminergic system is not involved in the observed age-related increase in extracellular basal glutamate levels. In contrast to basal efflux, potassium-evoked glutamate release was not altered with age. However, LY 163502 significantly inhibited stimulated glutamate release in 4-month-old rats. This inhibitory action was not observed at any other age. Sulpiride alone did not alter stimulated glutamate release, but it did block the inhibitory effect of LY 163502 in the 4-month-old rats. These results provide in vivo evidence for an age-related functional loss in the modulation of striatal glutamate release by dopamine D-2 receptors in addition to increased basal glutamate efflux, which is not related to D-2 receptor modulation. Such mechanisms could be important in the pathophysiology of striatal cell death during aging and age-related neurodegenerative diseases.