The applicant is interested in changes in dopaminergic neurons (primarily in the caudate-putamen) during aging and how these changes affect motor functions and learning. Results from his work during the previous funding period have focused his attention on the functional and anatomical heterogeneities within the dopamine system in the rat caudate-putamen. The lateral striatum (primate putamen) receives major innervation from the sensorimotor cortex; it also has a higher density of D-2 dopamine binding sites and is associated with greater increases in blood flow and 14C-2 deoxyglucose (DG) uptake in response to systemic apomorphine administration when compared with the medial striatum. The medial striatum (primate caudate nucleus accumbens), on the other hand, receives major innervations from the prefrontal cortex, hippocampus and other limbic structures and, thus, may be related to """"""""cognition."""""""" These differences may be important in both neuro-degenerative disorders and putative """"""""normal"""""""" aging humans. The applicant proposes to pursue these differences in lateral and medial striatum. Since it has been reported that both levels of dopamine and dopamine receptors decrease in the rat striatum as a function of age, he plans to investigate regional changes in both these parameters. Using HPLC, he proposes to examine the lateral, central and medial striatum for concentrations of dopamine and its major metabolites HVA and DOPAC. In the same regions, D-2 dopamine receptor numbers will be quantitated using both homogenate radioligand binding assays and digital subtraction autoradiography. The binding studies will be extended to include human striatum as well. The biochemical measurements will be correlated with behaviors which are thought to be mediated by striatal D-2 dopamine receptors. The project leader postulates that injection of dopamine receptor agonists directly into the lateral striatum should show a decline in postural deviation with age. Conversely, he proposes that injection of dopamine or transplantation of fetal tissue which secretes dopamine into the medial striatum should improve the age-related decline in performance of a learned spatial task.
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