The Effect of a New Water-Soluble Sedative-Hypnotic Drug, JM-1232(−), on Long-Term Potentiation in the CA1 Region of the Mouse Hippocampus

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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.CONCLUSION: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.

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