Effects of a cognition-enhancer, linopirdine (DuP 996), on M-type potassium currents (I-K(M)) and some other voltage- and ligand-gated membrane currents in rat sympathetic neurons

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