Age-related diminution of dopamine antagonist-stimulated vesamicol receptor binding

Previous studies of radiolabeled vesamicol receptor (VR) ligands suggest that the latter may be used in conjunction with dopamine D2 antagonists to measure changes in striatal cholinergic function. In this study, the effects of aging on vesicular acetylcholine storage/release were investigated with the high-affinity VR ligand (+)-meta-[125I)iodobenzyltrozamicol [(+)-[125I]MIBT].

Male Fischer 344 rats (aged 3 and 24 mo) were injected either with a vehicle or a D2 antagonist [haloperidol or S-(-)-eticlopride]. At prescribed intervals thereafter, all animals were intravenously injected with 10 microCi of (+)-[125I]MIBT. Three hours after radiotracer injection, the animals were killed and their brains dissected. The concentration of radiotracer in the striatum, cortex and cerebellum were then determined.

In control animals, comparable levels of (+)-[125I]MIBT were observed in corresponding brain regions of young adult and aged Fischer 344 rats. Moreover, in haloperidol- and S-(-)-eticlopride-treated young adult rats, striatal levels of (+)-[125I]MIBT were elevated by 35% and 66%, respectively, relative to controls. In contrast, haloperidol treatment failed to alter the striatal levels of (+)-[125I]MIBT in aged rats while S-(-)-eticlopride displayed a twofold reduction in potency in aged rats.

Aging is associated with a reduction in striatal cholinergic plasticity or striatal cholinergic reserve and that the D2-stimulated increase in VR ligand binding is a functionally relevant parameter.