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

1. Histaminergic depression of excitatory synaptic transmission in the rat dentate gyrus was investigated using extracellular and whole-cell patch-clamp recording techniques in vitro. 2. Application of histamine (10 mu M, 5 min) depressed synaptic transmission in the dentate gyrus for 1 h. This depression was blocked by the selective antagonist of histamine H-3 receptors, thioperamide (10 mu M). 3.The magnitude of the depression caused by histamine was inversely related to the extracellular Ca2+ concentration. Application of the N-type calcium channel blocker omega-conotoxin (0.5 or 1 mu M) or the P/Q-type calcium channel blocker omega-agatoxin (800 nM) did not prevent depression of synaptic transmission by histamine. 4. The potassium channel blocker 4-aminopyridine (4-AP, 100 mu M) enhanced synaptic transmission and reduced the depressant effect of histamine (10 mu M). 4-AP reduced the effect of histamine more in 2 mM extracellular calcium than in 4 mM extracellular calcium. 5. Histamine (10 mu M) did not affect the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and had only a small effect on their frequency. 6. Histaminergic depression was not blocked by an inhibitor of serine/threonine protein kinases, H7 (100 mu M), or by an inhibitor of tyrosine kinases, Lavendust in A (10 mu M). 7. Application of adenosine (20 mu M) or the adenosine A(1) agonist N-6-cyclopentyladenosine (CPA, 0.3 mu M) completely occluded the effect of histamine (10 mu M). We conclude that histamine, acting on histamine H-3 receptors, inhibits glutamate release by inhibiting presynaptic calcium entry via a direct G-protein-mediated inhibition of multiple calcium channels. Histamine H-3 receptors and adenosine A(1) receptors act upon a common final effector to cause presynaptic inhibition.