REDUCTION OF SPIKE FREQUENCY ADAPTATION AND BLOCKADE OF M-CURRENT IN RAT CA1 PYRAMIDAL NEURONS BY LINOPIRDINE (DUP-996), A NEUROTRANSMITTERRELEASE ENHANCER

1 Linopirdine (DuP 996) has been shown to enhance depolarization-induc ed release of several neurotransmitters in the CNS through a mechanism which may involve K+ channel blockade. The electrophysiological effec ts of linopirdine were therefore investigated directly, by use of conv entional voltage recording and single electrode voltage-clamp. 2 Linop irdine (10 mu M) reduced spike frequency adaptation (SFA) in rat hippo campal CA1 pyramidal neurones in vitro. The reduction of SFA comprised an increase in number of spikes and a reduction in inter-spike interv als after the first, but with no effect on time to first spike. Linopi rdine also caused a voltage-dependent depolarization of resting membra ne potential (RMP). 3 M-current (I-M), a current known to underlie SFA and to set RMP, was blocked by linopirdine in a reversible, concentra tion-dependent manner (IC50 = 8.5 mu M) This block was not reversed by atropine (10 mu M). 4 Linopirdine did not affect I-Q, the slow after- hyperpolarization following a spike train, or spike duration. 5 Linopi rdine may represent a novel class of K+ blocker with relative selectiv ity for the M-current. This block of I-M is consistent with the sugges tion from a previous study that linopirdine may affect a tetraethylamm onium-sensitive channel, and it could be speculated that I-M blockade may be involved with the enhancement of neurotransmitter release by li nopirdine.