CGS-21680C

In corticostriatal nerve terminals, glutamate release is stimulated by adenosine via A2A receptors (A2ARs) and simultaneously inhibited by endocannabinoids via CB1 receptors (CB1Rs). We previously identified presynaptic A2AR–CB1R heterotetrameric complexes in corticostriatal nerve terminals. We now explored the possible functional interaction between A2ARs 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 A2AR‐selective agonist CGS21680 (30 nM) and the A2AR‐selective antagonist SCH58261 (100 nM) dampened the inhibitory action of WIN55212‐2 in rat synaptosomes. Another A2AR‐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 A2AR KO mice of both CD‐1 and C57BL/6 strains. In rat striatal synaptosomal membranes, the binding of [3H]ZM241385 to A2ARs was not affected by cannabinoids. However, ZM241385 reduced the Bmax while CGS21680 and SCH58261 increased the KD of [3H]SR141716A binding to CB1R, indicating an A2AR‐ligand‐specific modulation of CB1R function. CB1R Bmax and KD were reduced in A2AR KO mice, whereas A2AR Bmax was smaller in CB1R KO mice. Altogether, our data reveal an intricate interdependence of presynaptic A2ARs and CB1Rs on striatal neuromodulation.