title: The effect of a new water-soluble sedative-hypnotic drug, JM-1232(-), on long-term potentiation in the CA1 region of the mouse hippocampus.
abstract: BACKGROUND
  JM-1232(-) {(-)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl-3,5,6,7-tetrahydrocyclopenta[f]isoindol-1(2H)-one} is a new water-soluble sedative-hypnotic drug with affinity for the benzodiazepine binding site on γ-aminobutyric acid A receptors. The effects of JM-1232(-) on synaptic transmission in the brain are not known. In the present study, we investigated the effects of JM-1232(-) on synaptic transmission, synaptic plasticity (i.e., long-term potentiation [LTP] and paired-pulse facilitation), and excitatory/inhibitory postsynaptic currents (EPSCs/IPSCs) of pyramidal neurons in the CA1 region of mouse hippocampal slices.
  
  
  METHODS
  We recorded Schaffer collateral-evoked field excitatory postsynaptic potentials and EPSCs and IPSCs of pyramidal neurons using whole-cell patch-clamp techniques in the CA1 region of mouse hippocampal slices.
  
  
  RESULTS
  JM-1232(-) had no significant effect on the field excitatory postsynaptic potentials. Application of JM-1232(-) for 20 minutes before theta-burst stimulation dose dependently impaired LTP. JM-1232(-) impaired paired-pulse facilitation. The benzodiazepine antagonist flumazenil abolished the inhibitory effect of JM-1232(-) on LTP and paired-pulse facilitation. JM-1232(-) had no effect on Schaffer collateral stimulation-evoked EPSCs, whereas it potentiated the amplitude and prolonged the decay of evoked IPSCs in CA1 pyramidal neurons. Flumazenil blocked the effect of JM-1232(-) on the amplitude and decay of evoked IPSCs. JM-1232(-) suppressed the action potential discharge in the CA1 pyramidal neurons during theta-burst stimulation, which was reversed by flumazenil.
  
  
  CONCLUSIONS
  JM-1232(-) enhances synaptic inhibition and impairs LTP and paired-pulse facilitation in area CA1 of the mouse hippocampus. These effects were mediated by benzodiazepine binding sites on γ-aminobutyric acid A receptors.
authors.affiliation: Department of Anesthesiology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. tisao@ndmc.ac.jp
authors.forename: Isao
authors.initials: I
authors.lastname: Takamatsu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: Ryuji
authors.initials: R
authors.lastname: Yonamine
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.forename: Tomiei
authors.initials: T
authors.lastname: Kazama
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects*; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D054833:Isoindoles / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D013826:Theta Rhythm
chemical_list: C534223:3-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-2-phenyl-3,5,6,7-tetrahydrocyclopenta(f)isoindol-1(2H)-one; D006993:Hypnotics and Sedatives; D054833:Isoindoles; D010879:Piperazines; D011963:Receptors, GABA-A