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 H-3 receptors (H(3)Rs) most likely located on the synaptic afferents to the nucleus. In this work we studied the effect of the activation of rat pallidal H(3)Rs 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 [H-3]-GABA ([H-3]-gamma-aminobutyric acid) or [H-3]-dopamine evoked by depolarization with high (20 mM) K+, but significantly reduced [H-3]-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 mu M 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 mu l, 100 mu M) 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 mu l, 1 mM). In free-moving rats the infusion of immepip (0.5 mu l; 10, 50 and 100 mu M) 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 mu l, 50 mu M) and apomorphine was partially prevented by the local injection of A-331440 (0.5 mu l, 1 mM) and was not additive to the turning evoked by the intra-pallidal injection of antagonists at ionotropic glutamate receptors (0.5 mu l, 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 H(3)Rs modulate glutamatergic transmission in rat globus pallidus and thus participate in the control of movement by basal ganglia. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.