Effect of FK960, a putative cognitive enhancer, on synaptic transmission in CA1 neurons of rat hippocampus.
The action of FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel cognitive enhancer, on excitatory synaptic transmission in the hippocampus was investigated. Excitatory postsynaptic potentials (EPSPs) and currents (EPSCs) were recorded intracellularly from CA1 neurons in rat hippocampus using the "blind patch" variant of whole-cell recording. FK960 (100 nM) significantly increased the amplitude of the EPSP, which was unchanged when changeover was made to control artificial cerebrospinal fluid (aCSF). FK960 had no significant action on membrane potential, input resistance, or the early GABAergic inhibitory postsynaptic current. The decay phase of the excitatory postsynaptic current was not significantly altered by exposure to FK960, indicating that the properties of desensitization and/or deactivation were unchanged and suggesting that the action of FK960 was unlikely to be the result of changes in the properties of the postsynaptic (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors. The quantal content of the EPSP (1/CV(2)) increased after exposure to FK960 but not to control aCSF. Methyllycaconitine or alpha-bungarotoxin blocked the modulatory action of FK960 on the EPSP, and the finding that these alpha 7-nicotinic acetylcholine receptor (alpha 7nAChR) antagonists were effective raises the possibility that FK960 up-regulates the contribution of acetylcholine to synaptic efficacy in the hippocampus. It is concluded that FK960 increases the quantal release of glutamate from Schaffer collateral-commissural nerve terminals in area CA1 of the hippocampus either by changing the ambient level of acetylcholine or by positively modulating the activity of alpha 7nAChRs located on glutamatergic nerve terminals.
Hodgkiss
J P
JP
Fujisawa Institute of Neuroscience, Department of Neuroscience, University of Edinburgh, Edinburgh, United Kingdom. Joseph.Hodgkiss@ed.ac.uk
Kelly
J S
JS
D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002038:Bungarotoxins / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001549:Benzamides; D002038:Bungarotoxins; C579165:Chrna7 protein, rat; C102991:N-(4-acetyl-1-piperazinyl) -4-fluorobenzamide monohydrate; D018377:Neurotransmitter Agents; D010879:Piperazines; D011619:Psychotropic Drugs; D018091:Receptors, AMPA; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; D000157:Aconitine