Functional roles of 5-hydroxytryptamine 3/4 receptors in neurons of rat dorsal motor nucleus of the vagus.
In neurons of dorsal motor nucleus of the vagus that is involved in the gastric motility and possibly emesis, application of 5-hydroxytryptamine produces membrane depolarization, and suppresses spike-repolarization and spike-afterhyperpolarization, suggesting divergent effects of 5-hydroxytryptamine through activating multiple subtypes of 5-hydroxytryptamine receptors. However, only the role of 5-hydroxytryptamine 2A receptors has been established to be responsible for the depolarization, and the mechanisms underlying the modulation of spikes remain unknown although a role of 5-hydroxytryptamine 4 receptors was implicated in modulations of spikes. There is now increasing evidence for the role of 5-hydroxytryptamine receptors in neurons involved in generating emesis following administration of anticancer drug. Since antagonists of 5-hydroxytryptamine 3/4 receptors are widely used as anti-emetic drugs, we have reevaluated the functional roles of 5-hydroxytryptamine 3/4 receptors of dorsal motor nucleus of the vagus neurons, especially in modulating transient outward currents that are presumed to be involved in spike-repolarization and spike-afterhyperpolarization. Whole-cell patch-clamp recordings were made from the dorsal motor nucleus of the vagus neurons, which were identified by a retrograde tracing method with dextran-tetramethylrhodamine-lysine injected into a bundle of abdominal vagus nerves. Under a voltage-clamp condition, dorsal motor nucleus of the vagus neurons expressed a prominent A-like current. The activation of 5-hydroxytryptamine 3 receptors reversibly increased the resting membrane conductance while the activation of 5-hydroxytryptamine 4 receptors led to an almost irreversible decrease in the A-like current. A long-lasting suppression of A-like current by transient activation of 5-hydroxytryptamine 4 receptors would result in a long-lasting increase in the excitability of dorsal motor nucleus of the vagus neurons, which might be involved in generation of the long-lasting facilitation of gastric motility or in generation of the long-lasting gastric relaxation through the activation of enteric non-adrenergic non-cholinergic neurons as implicated in the delayed emesis induced by anticancer drugs.
Fukushi
E
E
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido 1757, Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
Saito
M
M
Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka 565-0871, Japan.
Sato
H
H
Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka 565-0871, Japan.
Endo
T
T
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido 1757, Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
Hamaue
N
N
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido 1757, Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
Hirafuji
M
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido 1757, Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
Minami
M
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido 1757, Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
Kang
Y
Y
Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: kang@dent.osaka-u.ac.jp.
D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D008735:5-Methoxytryptamine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017829:Granisetron / Q000494:pharmacology; D066298:In Vitro Techniques; D008526:Medulla Oblongata / Q000166:cytology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D044406:Receptors, Serotonin, 5-HT3 / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology*; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014630:Vagus Nerve / Q000502:physiology*; D062366:para-Aminobenzoates
D010129:4-Aminobenzoic Acid; D008735:5-Methoxytryptamine; D002118:Calcium; D017829:Granisetron; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D062366:para-Aminobenzoates; C072790:2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester; C045918:2-methyl-5-HT