Modulation of spontaneous and stimulation-evoked transmitter release from rat sympathetic neurons by the cognition enhancer linopirdine: Insights into its mechanisms of action

The mechanisms by which the cognition enhancer linopirdine may affect trans mitter release were investigated in cultures of rat superior cervical gangl ion neurons. Overflow of previously incorporated [H-3]noradrenaline evoked by 10 mu M UTP or 0.1 mu M bradykinin was enhanced by linopirdine at greate r than or equal to 3 mu M, overflow evoked by 25 mM K+, 100 mu M nicotine, or 300 mu M ATP was enhanced by linopirdine at greater than or equal to 10 mu M, and overflow due to 40 mM K+ or electrical field stimulation was not altered by linopirdine, Ba2+ (0.3 mM) augmented the same types of stimulati on-evoked overflow to a similar extent as linopirdine, K+ (25 mM), nicotine (100 mu M), and ATP (300 mu M) triggered transmitter release in a partiall y tetrodotoxin-resistant manner, and the release-enhancing action of linopi rdine was lost in the presence of tetrodotoxin (1 mu M). Linopirdine (10 mu M) raised spontaneous tritium outflow and reduced currents through muscari nic K+ (K-M) channels with a similar time course. The secretagogue action o f linopirdine was concentration- and Ca2+-dependent and abolished by tetrod otoxin (1 mu M) or Cd2+ (100 mu M). Linopirdine (10 mu M) added to the part ial inhibition of K-M channels by 1 or 3 mM Ba2+ but not to the complete in hibition by 10 mM Ba2+. Likewise, the secretagogue action of 1 and 3 mM, bu t not that of 10 mM, Ba2+ was enhanced by linopirdine, These results indica te that linopirdine facilitates and triggers transmitter release via blocka de of K-M channels and suggest that these K+ channels are located at neuron al somata rather than at presynaptic sites.