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 microM) suppressed the ACh-induced acceleratory and GABA-induced inhibitory actions without affecting the excitatory actions of AMPA and NMDA. Under voltage-clamp 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 (V(H)) of -60 or 0 mV. Z-338 (>3 microM) 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 microM) 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 microM) 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.