Pre-synaptic histamine H₃ receptors modulate glutamatergic transmission in rat globus pallidus

The globus pallidus, a neuronal nucleus involved in the control of motor behavior, expresses high levels of histamine H₃ receptors (H₃Rs) most likely located on the synaptic afferents to the nucleus. In this work we studied the effect of the activation of rat pallidal H₃Rs on depolarization-evoked neurotransmitter release from slices, neuronal firing rate in vivo and turning behavior. Perfusion of globus pallidus slices with the selective H₃R agonist immepip had no effect on the release of [³H]-GABA ([³H]-γ-aminobutyric acid) or [³H]-dopamine evoked by depolarization with high (20 mM) K⁺, but significantly reduced [³H]-d-aspartate release (-44.8±2.6% and -63.7±6.2% at 30 and 100 nM, respectively). The effect of 30 nM immepip was blocked by 10 μM of the selective H₃R antagonist A-331440 (4'-[3-[(3(R)-dimethylamino-1-pyrrolidinyl]propoxy]-[1,1-biphenyl]-4'-carbonitrile). Intra-pallidal injection of immepip (0.1 μl, 100 μM) decreased spontaneous neuronal firing rate in anaesthetized rats (peak inhibition 68.8±10.3%), and this effect was reversed in a partial and transitory manner by A-331440 (0.1 μl, 1 mM). In free-moving rats the infusion of immepip (0.5 μl; 10, 50 and 100 μM) into the globus pallidus induced dose-related ipsilateral turning following systemic apomorphine (0.5 mg/kg, s.c.). Turning behavior induced by immepip (0.5 μl, 50 μM) and apomorphine was partially prevented by the local injection of A-331440 (0.5 μl, 1 mM) and was not additive to the turning evoked by the intra-pallidal injection of antagonists at ionotropic glutamate receptors (0.5 μl, 1 mM each of AP-5, dl-2-amino-5-phosphonovaleric acid, and CNQX, 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione). These results indicate that pre-synaptic H₃Rs modulate glutamatergic transmission in rat globus pallidus and thus participate in the control of movement by basal ganglia.