Histamine H3 Receptor Activation Counteracts Adenosine A2A Receptor-Mediated Enhancement of Depolarization-Evoked [3H]-GABA Release from Rat Globus Pallidus Synaptosomes

High levels of histamine H-3 receptors (H(3)Rs) are found in the globus pallidus (GP), a neuronal nucleus in the basal ganglia involved in the control of motor behavior. By using rat GP isolated nerve terminals (synaptosomes), we studied whether H3R activation modified the previously reported enhancing action of adenosine A(2A) receptor (A(2A)R) stimulation on depolarization-evoked [H-3]-GABA release. At 3 and 10 nM, the A(2A)R agonist CGS-21680 enhanced [H-3]-GABA release induced by high K+ (20 mM) and the effect of 3 nM CGS-21680 was prevented by the A(2A)R antagonist ZM-241385 (100 nM). The presence of presynaptic H(3)Rs was confirmed by the specific binding of N-alpha-[methyl-H-3]-histamine to membranes from GP synaptosomes (maximum binding, B-max, 1327 +/- 79 fmol/mg protein; dissociation constant, K-d, 0.74 nM), which was inhibited by the H3R ligands immepip, clobenpropit, and A-331440 (inhibition constants, K-i, 0.28, 8.53, and 316 nM, respectively). Perfusion of synaptosomes with the H3R agonist immepip (100 nM) had no effect on K+-evoked [H-3]-GABA release, but inhibited the stimulatory action of A(2A)R activation. In turn, the effect of immepip was blocked by the H3R antagonist clobenpropit, which had no significant effect of its own on K+-induced [H-3]-GABA release. These data indicate that H3R activation selectively counteracts the facilitatory action of A(2A)R stimulation on GABA release from striato-pallidal projections.