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We investigated the effects of the novel gastroprokinetic agent Z-338 on the actions of excitatory and inhibitory neurotransmitters on neurons in area postrema (AP). Iontophoretic applications of acetylcholine (ACh), AMPA and NMDA increased, while GABA suppressed the firing rates of AP neurons recorded by extracellular electrodes. Z-338 (10 µM) suppressed the ACh-induced acceleratory and GABA-induced inhibitory actions without affecting the excitatory actions of AMPA and NMDA. Under voltageclamp conditions, nicotine, NMDA, kainic acid (KA) and ATP evoked inward currents in dissociated single AP neurons recorded by whole-cell patch clamp technique, and GABA produced outward currents, at holding potentials (VH) of -60 or 0 mV. Z-338 (>3 µM) specifically suppressed the nicotine-and GABA-induced currents without affecting the currents induced by NMDA, KA and ATP. In addition, we found that Z-338 (30 µM) suppressed the spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from AP neurons in slice preparations. Experiments with microelectrode and histochemical methods revealed the presence of direct excitatory and di-synaptic inhibitory neural connections from AP to dorsal motor nucleus of the vagus (DMV). In some AP neurons, Z-338 (10 µM) enhanced the spontaneous firing rates recorded by extracellular electrode.The excitatory or inhibitory effects of Z-338 on the firing rates or actions of nicotine and GABA on AP neurons observed in the present study may explain the postmeal relaxation induced by Z-338 in patients with functional dyspepsia.

Key points Xenon (Xe) non‐competitively inhibited whole‐cell excitatory glutamatergic current (IGlu) and whole‐cell currents gated by ionotropic glutamate receptors (IAMPA, IKA, INMDA), but had no effect on inhibitory GABAergic whole‐cell current (IGABA). Xe decreased only the frequency of glutamatergic spontaneous and miniature excitatory postsynaptic currents and GABAergic spontaneous inhibitory postsynaptic currents without changing the amplitude or decay times of these synaptic responses. Xe decreased the amplitude of both the action potential‐evoked excitatory and the action potential‐evoked inhibitory postsynaptic currents (eEPSCs and eIPSCs, respectively) via a presynaptic inhibition in transmitter release. We conclude that the main site of action of Xe is presynaptic in both excitatory and inhibitory synapses, and that the Xe inhibition is much greater for eEPSCs than for eIPSCs. Abstract To clarify how xenon (Xe) modulates excitatory and inhibitory whole‐cell and synaptic responses, we conducted an electrophysiological experiment using the ‘synapse bouton preparation’ dissociated mechanically from the rat hippocampal CA3 region. This technique can evaluate pure single‐ or multi‐synapse responses and enabled us to accurately quantify how Xe influences pre‐ and postsynaptic aspects of synaptic transmission. Xe inhibited whole‐cell glutamatergic current (IGlu) and whole‐cell currents gated by the three subtypes of glutamate receptor (IAMPA, IKA and INMDA). Inhibition of these ionotropic currents occurred in a concentration‐dependent, non‐competitive and voltage‐independent manner. Xe markedly depressed the slow steady current component of IAMPA almost without altering the fast phasic IAMPA component non‐desensitized by cyclothiazide. It decreased current frequency without affecting the amplitude and current kinetics of glutamatergic spontaneous excitatory postsynaptic currents and miniature excitatory postsynaptic currents. It decreased the amplitude, increasing the failure rate (Rf) and paired‐pulse rate (PPR) without altering the current kinetics of glutamatergic action potential‐evoked excitatory postsynaptic currents. Thus, Xe has a clear presynaptic effect on excitatory synaptic transmission. Xe did not alter the GABA‐induced whole‐cell current (IGABA). It decreased the frequency of GABAergic spontaneous inhibitory postsynaptic currents without changing the amplitude and current kinetics. It decreased the amplitude and increased the PPR and Rf of the GABAergic action potential‐evoked inhibitory postsynaptic currents without altering the current kinetics. Thus, Xe acts exclusively at presynaptic sites at the GABAergic synapse. In conclusion, our data indicate that a presynaptic decrease of excitatory transmission is likely to be the major mechanism by which Xe induces anaesthesia, with little contribution of effects on GABAergic synapses.

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