Effects of Z-338, a novel gastroprokinetic agent, on the actions of excitatory and inhibitory neurotransmitters on neurons in area postrema

Abstract

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.

Effect of acotiamide on gastric emptying in healthy adult humans

“…Several recent studies suggested that the pharmacological potency of acotiamide was based on inhibition of acetylcholinesterase (AChE), regulation of muscarinic autoreceptors and regulation of gene expression of γ‐aminobutyric acid (GABA) transporters in the medulla oblongata . Akaike et al .…”

“…Akaike et al . reported that the excitatory or inhibitory effects of acotiamide on the firing rates of neurons or actions of nicotine and GABA on area postrema (AP) neurons may explain postmeal relaxation in rats. Seto et al .…”

Acotiamide, a novel gastroprokinetic for the treatment of patients with functional dyspepsia: postprandial distress syndrome

“…It also decreased the inhibitory action of GABA; however, this latter effect required relatively high concentrations of acotiamide in the slice preparations (3 vs 30 µM). The authors concluded that acotiamide modifies the firing of neurons of the AP largely by its antagonism of nicotinic receptors and, to some extent, GABA A receptors [25].…”

“…Increased cholinergic input from cholinergic interneurons to inhibitory motor neurons in the proximal stomach has the potential to induce such effects [3]. Alternatively, the effects of acotiamide on the AP neurons may also contribute to enhanced accommodation [25].…”

“…There is also evidence that it acts as an agonist on an Ach M 5 -like receptor on gastric myocytes [17]. The central effects, in the AP and on afferent vagal fibers, affect motility and counteract some stress-mediated changes in the brainstem [25]. These multiple mechanisms of action on different levels of FD pathogenesis make it a promising therapeutic option in this patient group.…”