Reduction of spike frequency adaptation and blockade of M-current in rat CA1 pyramidal neurones by linopirdine (DuP 996), a neurotransmitter release enhancer.
1. Linopirdine (DuP 996) has been shown to enhance depolarization-induced release of several neurotransmitters in the CNS through a mechanism which may involve K+ channel blockade. The electrophysiological effects of linopirdine were therefore investigated directly, by use of conventional voltage recording and single electrode voltage-clamp. 2. Linopirdine (10 microM) reduced spike frequency adaptation (SFA) in rat hippocampal CA1 pyramidal neurones in vitro. The reduction of SFA comprised an increase in number of spikes and a reduction in inter-spike intervals after the first, but with no effect on time to first spike. Linopirdine also caused a voltage-dependent depolarization of resting membrane potential (RMP). 3. M-current (IM), a current known to underlie SFA and to set RMP, was blocked by linopirdine in a reversible, concentration-dependent manner (IC50 = 8.5 microM). This block was not reversed by atropine (10 microM). 4. Linopirdine did not affect IQ, the slow after-hyperpolarization following a spike train, or spike duration. 5. Linopirdine may represent a novel class of K+ blocker with relative selectivity for the M-current. This block of IM is consistent with the suggestion from a previous study that linopirdine may affect a tetraethylammonium-sensitive channel, and it could be speculated that IM blockade may be involved with the enhancement of neurotransmitter release by linopirdine.
Aiken
S P
SP
DuPont Merck Pharmaceutical Company, Wilmington, DE 19880-0400, USA.
Lampe
B J
BJ
Murphy
P A
PA
Brown
B S
BS
D000200:Action Potentials / Q000187:drug effects; D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D007211:Indoles / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D026902:Potassium Channel Blockers; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats
D007211:Indoles; D018377:Neurotransmitter Agents; D026902:Potassium Channel Blockers; D011725:Pyridines; C061017:linopirdine