Adenosine stimulates glycogenolysis in mouse cerebral cortex: A possible coupling mechanism between neuronal activity and energy metabolism

Adenosine promotes a concentration-dependent hydrolysis of ³H-glycogen newly synthesized from ³H-glucose by mouse cerebral cortical slices. The EC₅₀ for this effect is 7 μM. Theophylline antagonizes the glycogenolysis induced by adenosine with an EC₅₀ of 80 μM. The rank-order of potencies of adenosine agonists is adenosine 5'-cyclopropyl-carboxamide > 2-chloroadenosine >> N⁶-cyclohexyladenosine = adenosine, suggesting that adenosine promotes glycogenolysis via receptors of the A₂ type. This contention is substantiated by the weak stereospecificity observed for the glycogenolytic action of D- and L-(phenylisopropyl)-adenosine. The glycogenolysis elicited by adenosine at 10 and 100 μM is inhibited by ouabain at 10 μM, a concentration of the cardiac glycoside not significantly affecting ³H-glycogen levels per se. Interestingly, the previously demonstrated glycogenolytic action of vasoactive intestinal peptide and of norepinephrine is also antagonized by ouabain. These results demonstrate the existence of a metabolic action of adenosine, which is sensitive to ouabain and appears to be mediated by A₂ receptors. The concentrations at which adenosine promotes glycogenolysis are of the same order of magnitude as those reached extracellularly by the nucleoside during neuronal depolarization. This set of observations therefore supports the notion that adenosine plays a modulatory role in the coupling between neuronal activity and energy metabolism in the CNS.