title: 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 microM UTP or 0.1 microM bradykinin was enhanced by linopirdine at > or =3 microM, overflow evoked by 25 mM K(-), 100 microM nicotine, or 300 microM ATP was enhanced by linopirdine at > or =10 microM, 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 microM), and ATP (300 microM) triggered transmitter release in a partially tetrodotoxin-resistant manner, and the release-enhancing action of linopirdine was lost in the presence of tetrodotoxin (1 microM). Linopirdine (10 microM) raised spontaneous tritium outflow and reduced currents through muscarinic K+ (K(M)) channels with a similar time course. The secretagogue action of linopirdine was concentration- and Ca2(+)-dependent and abolished by tetrodotoxin (1 microM) or Cd2+ (100 microM). Linopirdine (10 microM) added to the partial inhibition of K(M) 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(M) channels and suggest that these K+ channels are located at neuronal somata rather than at presynaptic sites.
authors.affiliation: Institute of Neuropharmacology, University of Vienna, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Kristufek
authors.forename: G
authors.initials: G
authors.lastname: Koth
authors.forename: A
authors.initials: A
authors.lastname: Motejlek
authors.forename: K
authors.initials: K
authors.lastname: Schwarz
authors.forename: S
authors.initials: S
authors.lastname: Huck
authors.forename: S
authors.initials: S
authors.lastname: Boehm
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D004347:Drug Interactions; D004558:Electric Stimulation; D007211:Indoles / Q000494:pharmacology*; D009116:Muscarine / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism; D014544:Uridine Triphosphate / Q000494:pharmacology
chemical_list: D007211:Indoles; D018377:Neurotransmitter Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011725:Pyridines; D014316:Tritium; D001464:Barium; D013779:Tetrodotoxin; D009538:Nicotine; D009116:Muscarine; D000255:Adenosine Triphosphate; C061017:linopirdine; D001920:Bradykinin; D014544:Uridine Triphosphate