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.