Modulation of Spontaneous and Stimulation‐Evoked Transmitter Release from Rat Sympathetic Neurons by the Cognition Enhancer Linopirdine: Insights into Its Mechanisms of Action

Abstract: The mechanisms by which the cognition enhancer linopirdine may affect transmitter release were investigated in cultures of rat superior cervical ganglion neurons. Overflow of previously incorporated [3H]noradrenaline evoked by 10 μM UTP or 0.1 μM bradykinin was enhanced by linopirdine at ∼3 μM, overflow evoked by 25 mM K+, 100 μM nicotine, or 300 μM ATP was enhanced by linopirdine at ∼10 μM, 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 stimulation-evoked overflow to a similar extent as linopirdine. K+ (25 mM), nicotine (100 μM), and ATP (300 μM) triggered transmitter release in a partially tetrodotoxin-resistant manner, and the release-enhancing action of linopirdine was lost in the presence of tetrodotoxin (1 μM). Linopirdine (10 μM) raised spontaneous tritium outflow and reduced currents through muscarinic K+ (KM) channels with a similar time course. The secretagogue action of linopirdine was concentration- and Ca2+-dependent and abolished by tetrodotoxin (1 μM) or Cd2+ (100 μM). Linopirdine (10 μM) added to the partial inhibition of KM channels by 1 or 3 mM Ba2+ but not to the complete inhibition by 10 mM Ba2+. Likewise, the secretagogue action of 1 and 3 mM, but not that of 10 mM, Ba2+ was enhanced by linopirdine. These results indicate that linopirdine facilitates and triggers transmitter release via blockade of KM channels and suggest that these K+ channels are located at neuronal somata rather than at presynaptic sites.