Action of the hyperpolarization-activated current (Ih) blocker ZD 7288 in hippocampal CA1 neurons.

The effects of ZD 7288, a "bradycardic" agent, in young rat hippocampal slices in vitro were studied. ZD 7288 (1-1000 microM) reduced the hyperpolarization-activated current (Ih) in CA1 pyramidal neurons by a voltage-independent blocking mechanism. Under current-clamp conditions, the bradycardic agent (10 microM) caused membrane hyperpolarization (by 5.9 +/- 0.5 mV) and a reduction of membrane conductance (by 17.9 +/- 4.1%). These data are consistent with the block of an inward current which is active at rest. The drug-induced hyperpolarization depressed the cell's excitability by increasing the threshold current necessary to induce firing. When the drug-induced hyperpolarization was compensated for by injection of a tonic depolarizing current, ZD 7288 caused a reduction of the inhibitory post-synaptic potential (IPSP) in EPSP-IPSP sequences. Since Cs+, another known blocker of Ih, is able to reverse long-term depression (LTD) of the CA3-CA1 synapse in hippocampal slices, we tested the effect of ZD 7288 on synaptic transmission. We found that ZD 7288 did not significantly modify LTD, suggesting that Cs+-induced inhibition of LTD maintenance is not directly related to block of Ih.