Reduction of spike frequency adaptation and blockade of M‐current in rat CA1 pyramidal neurones by linopirdine (DuP 996), a neurotransmitter release enhancer

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 μm) reduced spike frequency adaptation (SFA) in rat hippocampal CA1 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 μm). This block was not reversed by atropine (10 μm). 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.