Adenosine A 2A and histamine H 3 receptors interact at the cAMP/PKA pathway to modulate depolarization-evoked [ 3 H]-GABA release from rat striato-pallidal terminals.

We previously reported that the activation of histamine H3 receptors (H3 Rs) selectively counteracts the facilitatory action of adenosine A2A receptors (A2A Rs) on GABA release from rat globus pallidus (GP) isolated nerve terminals (synaptosomes). In this work, we examined the mechanisms likely to underlie this functional interaction. Three possibilities were explored: (a) changes in receptor affinity for agonists induced by physical A2A R/H3 R interaction, (b) opposite actions of A2A Rs and H3 Rs on depolarization-induced Ca2+ entry, and (c) an A2A R/H3 R interaction at the level of adenosine 3',5'-cyclic monophosphate (cAMP) formation. In GP synaptosomal membranes, H3 R activation with immepip reduced A2A R affinity for the agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride hydrate (CGS-21680) (Ki control 4.53 nM; + immepip 9.32 nM), whereas A2A R activation increased H3 R affinity for immepip (Ki control 0.63 nM; + CGS-21680 0.26 nM). Neither A2A R activation nor H3 R stimulation modified calcium entry through voltage-gated calcium channels in GP synaptosomes, as evaluated by microfluorometry. A2A R-mediated facilitation of depolarization-evoked [2,3-3 H]-γ-aminobutyric acid ([3 H]-GABA) release from GP synaptosomes (130.4 ± 3.6% of control values) was prevented by the PKA inhibitor H-89 and mimicked by the adenylyl cyclase activator forskolin or by 8-Bromo-cAMP, a membrane permeant cAMP analogue (169.5 ± 17.3 and 149.5 ± 14.5% of controls). H3 R activation failed to reduce the facilitation of [3 H]-GABA release induced by 8-Bromo-cAMP. In GP slices, A2A R activation stimulated cAMP accumulation (290% of basal) and this effect was reduced (- 75%) by H3 R activation. These results indicate that in striato-pallidal nerve terminals, A2A Rs and H3 Rs interact at the level of cAMP formation to modulate PKA activity and thus GABA release.