On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyrus

摘要

class="enumerated" style="list-style-type:decimal">Histaminergic depression of excitatory synaptic transmission in the rat dentate gyrus was investigated using extracellular and whole-cell patch-clamp recording techniques in vitro.Application of histamine (10 μm, 5 min) depressed synaptic transmission in the dentate gyrus for 1 h. This depression was blocked by the selective antagonist of histamine H3 receptors, thioperamide (10 μm).The magnitude of the depression caused by histamine was inversely related to the extracellular Ca²⁺ concentration. Application of the N-type calcium channel blocker ω-conotoxin (0.5 or 1 μm) or the P/Q-type calcium channel blocker ω-agatoxin (800 nm) did not prevent depression of synaptic transmission by histamine.The potassium channel blocker 4-aminopyridine (4-AP, 100 μm) enhanced synaptic transmission and reduced the depressant effect of histamine (10 μm). 4-AP reduced the effect of histamine more in 2 mm extracellular calcium than in 4 mm extracellular calcium.Histamine (10 μm) did not affect the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and had only a small effect on their frequency.Histaminergic depression was not blocked by an inhibitor of serine/threonine protein kinases, H7 (100 μm), or by an inhibitor of tyrosine kinases, Lavendustin A (10 μm).Application of adenosine (20 μm) or the adenosine A1 agonist N⁶-cyclopentyladenosine (CPA, 0.3 μm) completely occluded the effect of histamine (10 μm).We conclude that histamine, acting on histamine H3 receptors, inhibits glutamate release by inhibiting presynaptic calcium entry, via a direct G-protein-mediated inhibition of multiple calcium channels. Histamine H3 receptors and adenosine A1 receptors act upon a common final effector to cause presynaptic inhibition.