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 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.
Kristufek
D
D
Institute of Neuropharmacology, University of Vienna, Austria.
Koth
G
G
Motejlek
A
A
Schwarz
K
K
Huck
S
S
Boehm
S
S
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
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