RECEPTOR-SELECTIVE AND AGE-SELECTIVE EFFECTS OF DOPAMINE OXIDATION ONRECEPTOR-G-PROTEIN INTERACTIONS IN THE STRIATUM

The striatum contains a high concentration of oxidizable dopamine (DA) , and the aged organism shows a decreased ability to respond to oxidat ive stress (OS), making this area extremely vulnerable to free radical insult. To determine the receptor specificity of this putative increa se in OS sensitivity, striatal slices from 6- and 24-month-old animals were incubated (30 min, 37 degrees C) in a modified Krebs medium cont aining 0 to 500 mu M DA with or without a preincubation (15 min) in a nitrone trapping agent, 1 or 5 mM alpha-phenyl-n-tert-butyl nitrone (P EN), and changes in low K-m GTPase activity (an index of receptor-C pr otein coupling/uncoupling) assessed in muscarinic, 5-HT1A D-1, and D-2 receptors stimulated with carbachol, 8 OH-DPAT-HBr, SKF 38393, or qui nelorane, respectively. DA exposure induced selective decreases in the stimulated activity in all of these receptor systems, and an overall increase in conjugated dienes (56%) of the young. In the case of carba chol and 8 OH-DPAT-HBr, the DA-induced deficits in GTPase stimulation were seen primarily in the young (61 and 32%, respectively), while DA- induced deficits in quinelorane (D-2) stimulation were seen in both ag e groups. In the case of SKF 38393-stimulation (D-1) the DA-induced de ficits were higher in the striatal tissue from the old. The DA-induced decreases in carbachol stimulated GTPase activity in the tissue from the young could be prevented by pretreatment with PEN or the DA uptake inhibitor, nomifensin. No effect of nomifensin was seen in the old, b ecause their DA uptake mechanisms were already compromised. These resu lts suggest that although age-related declines in DA uptake may provid e some protection against the OS effects in muscarinic or 5-HT1A recep tors, other factors may increase the vulnerability of DA neurons to OS , even with reductions in DA uptake. Published by Elsevier Science Inc .