Denervation and hyperinnervation in the nervous system of diabetic animals: III. Functional alterations of G proteins in diabetic encephalopathy

G protein-mediated effects on cAMP production were evaluated in the corpus striatum of diabetic rats 5 and 14 weeks after alloxan injection by measuring both D1-receptor-induced stimulation and D2-receptor-mediated inhibition of adenylate-cyclase activity. At 5 weeks of diabetes, no obvious alterations of G protein functions were detected. Both dopamine-stimulated adenylate cyclase and bromocriptine-induced inhibition of enzyme activity were indeed similar in control and diabetic animals. Fourteen weeks after alloxan injection, profound alterations were observed. Dopamine-stimulated cAMP production was markedly increased in diabetic rats, whereas bromocriptine ability to reduce cAMP formation was almost abolished at this late stage of diabetes. Hypoactivity of G(i)/G(o) proteins was also confirmed by the reduced ability of the GTP non-hydrolyzable analog GTP-γ-S to inhibit forskolin-stimulation of adenylate cyclase. These results show an apparent functional imbalance between G(s) and G(i)/G(o)-mediated transduction mechanisms, with an increased efficacy of G(s) activity likely due to the loss of G(i)/G(o) inhibitory functions. Concomitantly with such transductional alteration detected in chronic diabetes, we observed a marked increase of the striatal content of met-enkephalin, which is known to utilize G(i)/G(o) proteins for inhibition of adenylate cyclase. The measurement of other transmitters (vaso-active intestinal peptide, substance P, serotonin, noradrenaline, and dopamine) did not reveal any difference with respect to controls. The observed transductional defect in diabetic animals and the increased content and/or hyperinnervation by the met-enkephalinergic system could be correlated as mutual compensatory mechanisms.