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 microM) 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 microM). This block was not reversed by atropine (10 microM). 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.

Linopirdine reduces stimulus intensity threshold for induction of long-term potentiation in the Schaffer collateral/CA1 pathway in rat hippocampal slices.

Linopirdine, a putative cognition enhancing agent, increases neurotransmitter release and blocks M-current in rat brain. Its effects on long-term potentiation (LTP) in the Schaffer collateral/CA1 pathway were investigated using standard, extracellular recording techniques in rat hippocampal slice preparation. When using a half maximal stimulus intensity for tetanic stimulation, a 30 min exposure to 3 or 10 microM linopirdine exerted no significant effect on excitatory postsynaptic potential (EPSP) slope, post-tetanic potentiation or LTP. In contrast, when a weak stimulus was employed, linopirdine enhanced the incidence and amplitude of LTP in a dose-dependent manner. These results indicate that linopirdine reduced stimulus intensity threshold for induction of LTP, an effect which may be mediated by its ability to enhance presynaptic glutamate release and cause CA1 membrane depolarization.