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

Ritchie E. Brown and Helmut L. Haas

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 -conotoxin (0·5 or 1 µM) or the P/Q-type calcium channel blocker -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.

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