Endogenous Adenosine Regulates the Apparent Efficacy of 1-Aminocyclopentyl-1S,3R-Dicarboxylate Inhibition of Forskolin-Stimulated Cyclic AMP Accumulation in Rat Cerebral Cortical Slices

Abstract: In rat cerebral cortical slices, the 1-aminocyclopentyl-1 S ,3 R -dicarboxylate (1 S ,3 R -ACPD) isomer of the selective metabotropic excitatory amino acid agonist ACPD inhibited forskolin-stimulated cyclic AMP (cAMP) accumulation in a concentration-dependent manner with a maximal inhibition of 51 ± 3% and a half-maximally effective concentration of 8.8 ± 3.4 μ M . Similarly, 1 R ,3 S -ACPD inhibited the forskolin response in a concentration-dependent manner, but with an inhibition of 80 ± 5% at 3 μ M . In addition to inhibiting forskolin-stimulated cAMP levels, 1 S ,3 R -ACPD, but not 1 R ,3 S -ACPD, enhanced the cAMP response to A_2b adenosine receptor activation. In the presence of 1.2 U/ml of adenosine deaminase (included to reduce the contribution of endogenous adenosine), the efficacy of 1 S ,3 R -ACPD was increased (88 ± 3% inhibition), but the potency was unchanged. The adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine also increased the inhibitory effect of 100 μ M 1 S ,3 R -ACPD, from 57 ± 1 to 78 ± 5%. These results indicate that endogenous adenosine plays an important role in regulating the apparent efficacy of 1 S ,3 R -ACPD inhibition of forskolin-stimulated cAMP accumulation in rat cerebral cortical slices and that previous studies in rat hippocampus and hypothalamus in the absence of added adenosine deaminase may have underestimated the efficacy of this compound.