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

Abstract

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 rH]noradrenaline evoked by 10 pM UTP or 0.1 pM bradykinin was enhanced by linopirdine at 2 3 pM, overflow evoked by 25 mM K+, 100 pM nicotine, or 300 pM ATP was enhanced by linopirdine at 210 pM, 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 pM), and ATP (300 pM) triggered transmitter release in a partially tetrodotoxin-resistant manner, and the release-enhancing action of linopirdine was lost in the presence of tetrodotoxin (1 pM). Linopirdine (1 0 pM) raised spontaneous tritium outflow and reduced currents through muscarinic Kf ( K, ) channels with a similar time course. The secretagogue action of linopirdine was concentration-and Ca2+-dependent and abolished by tetrodotoxin (1 pM) or Cd2+ (100 pM). Linopirdine (10 p l d ) added to the partial inhibition of K , 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 K , channels and suggest that these K+ channels are located at neuronal somata rather than at presynaptic sites. Key Words: Linopirdine-Ba'+-Rat superior cervical ganglion neurons-Muscarinic K+ channels-Noradrenaline release.

Functions of neuronal P2Y receptors

“…With respect to KCNQ channels, contrasting results have been obtained. In peripheral neurons, no evidence could be obtained that these ion channels are involved in action potential-evoked noradrenaline release [101,108]. However, in central synaptosomes, modulators of these ion channels were found to affect the release of various transmitters [122].…”

Distribution of M-channel subunits KCNQ2 and KCNQ3 in rat hippocampus

“…Thus, in sympathetic neurons, linopirdine indeed triggered noradrenaline release, but this effect was abolished by tetrodotoxin and was thus suggested as not mediated by a presynaptic mechanism (Kristufek et al, 1999; Lechner et al, 2003). Likewise, inhibition of M currents via M 1 receptors triggered noradrenaline release in a similar tetrodotoxin-sensitive manner, whereas retigabine was reported not to affect spontaneous or electrically evoked release of tritiated noradrenaline (Lechner et al, 2003).…”

Kv7 Channels: Function, Pharmacology and Channel Modulators

“…Thus linopirdine, XE991 and DMP543 had been known to enhance the release of various neurotransmitters, including acetylcholine, in a stimulus-evoked manner using both in vitro release and in vivo microdialysis methods [167][168][169][170]. Linopirdine and XE991 have also been shown to block the native M-current [71,171] and cloned neuronal K v 7 channels [10], and this mechanism is purported to mediate the stimulus-evoked release of neurotransmitters by these compounds [172]. By enhancing acetylcholine release it is also anticipated that such compounds may have cognition enhancing properties, and for linopirdine in particular the data in preclinical studies suggests that this is the case.…”