1 Linopirdine (DuP 996) has been shown to enhance depolarization-induced release of several neurotransmitters in the CNS through a mechanism which may involve K+ channel blockade. The electrophysiological effects of linopirdine were therefore investigated directly, by use of conventional voltage recording and single electrode voltage-clamp.2 Linopirdine (10 gM) reduced spike frequency adaptation (SFA) in rat hippocampal CAl pyramidal neurones in vitro. The reduction of SFA comprised an increase in number of spikes and a reduction in inter-spike intervals after the first, but with no effect on time to first spike. Linopirdine also caused a voltage-dependent depolarization of resting membrane potential (RMP). 3 M-current (IM), a current known to underlie SFA and to set RMP, was blocked by linopirdine in a reversible, concentration-dependent manner (IC50 = 8.5 gM). This block was not reversed by atropine (10 gM).4 Linopirdine did not affect IQ, the slow after-hyperpolarization following a spike train, or spike duration. 5 Linopirdine may represent a novel class of K+ blocker with relative selectivity for the M-current. This block of IM is consistent with the suggestion from a previous study that linopirdine may affect a tetraethylammonium-sensitive channel, and it could be speculated that IM blockade may be involved with the enhancement of neurotransmitter release by linopirdine.

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