Cannabinoid CB(1) and adenosine A(1) receptors independently inhibit hippocampal synaptic transmission

Adenosine A(1) and cannabinoid CB(1) receptors are affected by drugs widely consumed by humans, as it is the case for caffeine, an adenosine receptor antagonist, and tetrahydrocannabinol, a cannabinoid receptor agonist. These receptors are present in the hippocampus and inhibit neurotransmitter release by operating similar transduction mechanisms. We, therefore, evaluated if they cross-talk to modulate synaptic transmission in the hippocampus. To do so, field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 area of rat hippocampal slices and the consequences of activation or blockade of cannabinoid CB(1) or adenosine A(1) receptors upon neuromodulation exerted by the other receptor were assessed. The cannabinoid CB(1) receptor agonist, WIN55212-2 (300nM), slowly decreased ( congruent with40%) the fEPSP slope, while the adenosine A(1) receptor agonist, cyclopenthyladenosine (CPA, 15nM) rapidly decreased ( congruent with50%) it. Blockade of cannabinoid CB(1) receptors with AM251 (1microM) did not influence the adenosine A(1) receptor-mediated inhibition of synaptic transmission. Blockade of adenosine A(1) receptors with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 50nM) did not affect the inhibition perpetrated by cannabinoid CB(1) receptor activation. When both receptors were simultaneously activated (5nM CPA plus 300nM WIN55212-2) the net inhibition of synaptic transmission was about the sum of the effect of each drug applied independently. These results indicate independent synaptic transmission modulation by adenosine A(1) and cannabinoid CB(1) receptors at the hippocampus, suggesting that availability of G-proteins coupled to each receptor and availability of other signalling molecules involved in their transducing pathways, are not limiting factors for their modulatory role.