The Combined Inhibitory Effect of the Adenosine A1and Cannabinoid CB1Receptors on cAMP Accumulation in the Hippocampus Is Additive and Independent of A1Receptor Desensitization

Abstract

Adenosine A1and cannabinoid CB1receptors are highly expressed in hippocampus where they trigger similar transduction pathways. We investigated how the combined acute activation of A1and CB1receptors modulates cAMP accumulation in rat hippocampal slices. The CB1agonist WIN55212-2 (0.3–30 μM) decreased forskolin-stimulated cAMP accumulation with an EC50of 6.6 ± 2.7 μM and anEmax⁡of 31% ± 2%, whereas for the A1agonist, N6-cyclopentyladenosine (CPA, 10–150 nM), an EC50of 35 ± 19 nM, and anEmax⁡of 29% ± 5 were obtained. The combined inhibitory effect of WIN55212-2 (30 μM) and CPA (100 nM) on cAMP accumulation was 41% ± 6% (n=4), which did not differ (P>0.7) from the sum of the individual effects of each agonist (43% ± 8%) but was different (P<0.05) from the effects of CPA or WIN55212-2 alone. Preincubation with CPA (100 nM) for 95 min caused desensitization of adenosine A1activity, which did not modify the effect of WIN55212-2 (30 μM) on cAMP accumulation. In conclusion, the combined effect of CB1and A1receptors on cAMP formation is additive and CB1receptor activity is not affected by short-term A1receptor desensitization.