Comparing adenosine A 2A receptor modulation of cannabinoid CB ₁ receptor‐mediated inhibition of GABA and glutamate release in rodent striatal nerve terminals

In corticostriatal nerve terminals, glutamate release is stimulated by adenosine via A 2A receptors (A 2A Rs) and simultaneously inhibited by endocannabinoids via CB 1 receptors (CB 1 Rs). We previously identified presynaptic A 2A R–CB 1 R heterotetrameric complexes in corticostriatal nerve terminals. We now explored the possible functional interaction between A 2A Rs and CB 1 Rs in purified striatal GABAergic nerve terminals (synaptosomes) and compared these findings with those on the release of glutamate. In the striatal synaptosomes of rats and wild‐type mice, the synthetic cannabinoid receptor agonist WIN55212‐2 (10–1000 nM) attenuated the Ca 2+ ‐dependent, high‐K + ‐evoked release of γ‐[2,3‐ 3 H(N)]‐aminobutyric acid ([ 3 H]GABA) and [ 3 H]glutamate. WIN55212‐2 did not affect the evoked release of either neurotransmitter under CB 1 R blockade by AM251 or O‐2050 or in CB 1 R knockout (KO) mice. The A 2A R‐selective agonist CGS21680 (30 nM) and the A 2A R‐selective antagonist SCH58261 (100 nM) dampened the inhibitory action of WIN55212‐2 in rat synaptosomes. Another A 2A R‐selective antagonist, ZM241385 (100 nM), abolished the inhibition by WIN55212‐2 of the evoked release of both [ 3 H]GABA and [ 3 H]glutamate. Surprisingly, WIN55212‐2 also failed to inhibit the evoked release of [ 3 H]GABA but not of [ 3 H]glutamate in A 2A R KO mice of both CD‐1 and C57BL/6 strains. In rat striatal synaptosomal membranes, the binding of [ 3 H]ZM241385 to A 2A Rs was not affected by cannabinoids. However, ZM241385 reduced the B max while CGS21680 and SCH58261 increased the K D of [ 3 H]SR141716A binding to CB 1 R, indicating an A 2A R‐ligand‐specific modulation of CB 1 R function. CB 1 R B max and K D were reduced in A 2A R KO mice, whereas A 2A R B max was smaller in CB 1 R KO mice. Altogether, our data reveal an intricate interdependence of presynaptic A 2A Rs and CB 1 Rs on striatal neuromodulation.