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