Histamine H(3) Receptor Activation Modulates Glutamate Release in the Corticostriatal Synapse by Acting at Ca(V)2.1 (P/Q-Type) Calcium Channels and GIRK (K(IR)3) Potassium Channels.

The striatum is innervated by histaminergic fibers and expresses a high density of histamine H(3) receptors (H(3)Rs), present on medium spiny neurons (MSNs) and corticostriatal afferents. In this study, in sagittal slices from the rat dorsal striatum, excitatory postsynaptic potentials (EPSPs) were recorded in MSNs after electrical stimulation of corticostriatal axons. The effect of H(3)R activation and blockers of calcium and potassium channels was evaluated with the paired-pulse facilitation protocol. In the presence of the H(3)R antagonist/inverse agonist clobenpropit (1 μM), the H(3)R agonist immepip (1 μM) had no effect on the paired-pulse ratio (PPR), but in the absence of clobenpropit, immepip induced a significant increase in PPR, accompanied by a reduction in EPSP amplitude, suggesting presynaptic inhibition. The blockade of Ca(V)2.1 (P/Q-type) channels with ω-agatoxin TK (400 nM) increased PPR and prevented the effect of immepip. The Ca(V)2.2 (N-type) channel blocker ω-conotoxin GVIA (1 μM) also increased PPR, but did not occlude the immepip action. Functional K(IR)3 channels are present in corticostriatal terminals, and in experiments in which immepip increased PPR, the K(IR)3 blocker tertiapin-Q (30 nM) prevented the effect of the H(3)R agonist. These results indicate that the presynaptic modulation by H(3)Rs of corticostriatal synapses involves the inhibition of Ca(v)2.1 calcium channels and the activation of K(IR)3 potassium channels.