Re. Brown et Hl. Haas, On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyrus, J PHYSL LON, 515(3), 1999, pp. 777-786
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.