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_2ARs) and simultaneously inhibited by endocannabinoids via CB₁ receptors (CB₁Rs). We previously identified presynaptic A_2AR-CB₁R heterotetrameric complexes in corticostriatal nerve terminals. We now explored the possible functional interaction between A_2ARs and CB₁Rs 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 Ca²⁺-dependent, high-K⁺-evoked release of γ-[2,3-³H(N)]-aminobutyric acid ([³H]GABA) and [³H]glutamate. WIN55212-2 did not affect the evoked release of either neurotransmitter under CB₁R blockade by AM251 or O-2050 or in CB₁R knockout (KO) mice. The A_2AR-selective agonist CGS21680 (30 nM) and the A_2AR-selective antagonist SCH58261 (100 nM) dampened the inhibitory action of WIN55212-2 in rat synaptosomes. Another A_2AR-selective antagonist, ZM241385 (100 nM), abolished the inhibition by WIN55212-2 of the evoked release of both [³H]GABA and [³H]glutamate. Surprisingly, WIN55212-2 also failed to inhibit the evoked release of [³H]GABA but not of [³H]glutamate in A_2AR KO mice of both CD-1 and C57BL/6 strains. In rat striatal synaptosomal membranes, the binding of [³H]ZM241385 to A_2ARs was not affected by cannabinoids. However, ZM241385 reduced the B_max while CGS21680 and SCH58261 increased the K_D of [³H]SR141716A binding to CB₁R, indicating an A_2AR-ligand-specific modulation of CB₁R function. CB₁R B_max and K_D were reduced in A_2AR KO mice, whereas A_2AR B_max was smaller in CB₁R KO mice. Altogether, our data reveal an intricate interdependence of presynaptic A_2ARs and CB₁Rs on striatal neuromodulation.