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-cla mp recording techniques in vitro. 2. Application of histamine (10 mu M, 5 min) depressed synaptic transmissio n in the dentate gyrus for 1 h. This depression was blocked by the selectiv e 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 ch annel blocker omega-agatoxin (800 nM) did not prevent depression of synapti c 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 calciu m 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 freque ncy. 6. Histaminergic depression was not blocked by an inhibitor of serine/threo nine 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-cyc lopentyladenosine (CPA, 0.3 mu M) completely occluded the effect of histami ne (10 mu M). We conclude that histamine, acting on histamine H-3 receptors, inhibits glu tamate release by inhibiting presynaptic calcium entry via a direct G-prote in-mediated inhibition of multiple calcium channels. Histamine H-3 receptor s and adenosine A(1) receptors act upon a common final effector to cause pr esynaptic inhibition.