Ih channels as modulators of presynaptic terminal function: ZD7288 increases NMDA-evoked [3H]-noradrenaline release...

Recent observations indicate the presence of hyperpolarization-activated cation channels (I(h) channels) in presynaptic terminals of central neurons, but their functional impact is still unclear. To investigate whether there are operative I(h) channels on presynaptic terminals of noradrenergic neurons, the effect of the I(h) channel blocker ZD7288 on the N-methyl-D-aspartate (NMDA)-evoked [3H]-noradrenaline release ([3H]-NA release) was tested. Neocortical slices of the rat, preloaded with [(3)H]-NA, were superfused in the presence of TTX (0.32 microM) and stimulated twice by addition of 300 microM NMDA. Application of 1 and 10 microM ZD7288 increased the NMDA-evoked [(3)H]-NA release by 29 and 44%, respectively, in the presence of 3 mM external K+. Elevation of external K+ to 6 mM significantly reduced the increasing effect of 10 microM ZD7288 to 15% only. Our results indicate the presence of I(h) channels on presynaptic terminals of noradrenergic neurons and suggest that presynaptic I(h) channels may attenuate transmitter release, at least under the present test conditions.