EFFECTS OF A COGNITION-ENHANCER, LINOPIRDINE (DUP-996), ON M-TYPE POTASSIUM CURRENTS (I-K(M)) AND SOME OTHER VOLTAGE-GATED AND LIGAND-GATEDMEMBRANE CURRENTS IN RAT SYMPATHETIC NEURONS

Linopirdine is a cognition enhancer which augments depolarization-indu ced transmitter release in the cortex and which is under consideration for potential treatment of Alzheimer's disease. It has previously bee n reported to inhibit M-type K+ currents in rat hippocampal neurons. I n the present experiments we have tested its effect on whole-cell M-cu rrents and single M-channels, and on a range of other membrane current s, in dissociated rat superior cervical sympathetic ganglion cells. Li nopirdine inhibited the whole-cell M-current with an IC50 of 3.4 mu M and blocked M-channels recorded in excised outside-out membrane patche s but not in inside-out patches. This suggests that linopirdine direct ly blocks M-channels from the outside. It was much less effective in i nhibiting other voltage-gated potassium currents [delayed rectifier (I -K(V)), IC50 63 mu M; transient (I-A) current, IC50 69 mu M] and produ ced no detectable inhibition of the fast and slow Ca2+-activated K+ cu rrents I-C and I-AHP or of a hyperpolarization-activated cation curren t (I-Q/I-h) at 10-30 mu M. However, it reduced acetylcholine-activated nicotinic currents and GABA-activated Cl- currents with IC50 values o f 7.6 and 26 mu M respectively. It is concluded that linopirdine shows some 20-fold selectivity for M-channels among different K+ channels b ut can also block some transmitter-gated channels. The relationship be tween M-channel block and the central actions of linopirdine are discu ssed.