Histamine H3 Receptor Activation CounteractsAdenosine A2A Receptor-Mediated Enhancement of Depolarization-Evoked3H-GABA Release from Rat Globus Pallidus Synaptosomes

摘要

High levels of histamine H3 receptors (H3Rs) 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 A2A receptor (A2AR) stimulation on depolarization-evoked [³H]-GABA release. At 3 and 10 nM, the A2AR agonist CGS-21680 enhanced [³H]-GABA release induced by high K⁺ (20 mM) and the effect of 3 nM CGS-21680 was prevented by the A2AR antagonist ZM-241385 (100 nM). The presence of presynaptic H3Rs was confirmed by the specific binding of N-α-[methyl-³H]-histamine to membranes from GP synaptosomes (maximum binding, Bmax, 1327 ± 79 fmol/mg protein; dissociation constant, Kd, 0.74 nM), which was inhibited by the H3R ligands immepip, clobenpropit, and A-331440 (inhibition constants, Ki, 0.28, 8.53, and 316 nM, respectively). Perfusion of synaptosomes with the H3R agonist immepip (100 nM) had no effect on K⁺-evoked[³H]-GABA release, but inhibited the stimulatory actionof A2AR activation. In turn, the effect of immepip wasblocked by the H3R antagonist clobenpropit, which had nosignificant effect of its own on K⁺-induced [³H]-GABA release. These data indicate that H3R activationselectively counteracts the facilitatory action of A_2ARstimulation on GABA release from striato-pallidal projections.