The Combined Inhibitory Effect of the Adenosine A(1) and Cannabinoid CB(1) Receptors on cAMP Accumulation in the Hippocampus Is Additive and Independent of A(1) Receptor Desensitization

Adenosine A(1) and cannabinoid CB(1) receptors are highly expressed in hippocampus where they trigger similar transduction pathways. We investigated how the combined acute activation of A(1) and CB(1) receptors modulates cAMP accumulation in rat hippocampal slices. The CB(1) agonist WIN55212-2 (0.3–30 μM) decreased forskolin-stimulated cAMP accumulation with an EC(50) of 6.6 ± 2.7 μM and an E (max⁡) of 31% ± 2%, whereas for the A(1) agonist, N(6)-cyclopentyladenosine (CPA, 10–150 nM), an EC(50) of 35 ± 19 nM, and an E (max⁡) 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 A(1) activity, which did not modify the effect of WIN55212-2 (30 μM) on cAMP accumulation. In conclusion, the combined effect of CB(1) and A(1) receptors on cAMP formation is additive and CB(1) receptor activity is not affected by short-term A(1) receptor desensitization.