5-HT4 receptors exert a frequency-related facilitatory control on dorsal raphé nucleus 5-HT neuronal activity.
We investigated, using single-unit recordings in chloral hydrate-anaesthetized rats, the role of serotonin 4 (5-HT4) receptors in the control of dorsal raphé nucleus (DRN) 5-HT neuron activity. About one-half (36) of the 76 neurons recorded were affected by either the preferential 5-HT4 agonist cisapride (500 and 1000 micro g/kg, i.v.) or the selective 5-HT4 antagonist, GR 125487 (200- 2000 micro g/kg, i.v.). Responding neurons displayed a significantly higher mean basal firing rate (1.93 +/- 0.1 Hz) than non-responders (1.31 +/- 0.1 Hz). The firing rate of responding 5-HT neurons was enhanced dose-dependently by cisapride (+47 and +94% at 500 and 1000 micro g/kg, respectively), an effect abolished by GR 125487 (500 micro g/kg) and reduced by the 5-HT4 antagonist, SDZ 205557 (500 micro g/kg, i.v). Conversely, GR 125487 induced a dose-dependent inhibition of responders activity, which was almost completely suppressed at the dose of 2000 micro g/kg. In a separate set of experiments, the selective 5-HT4 agonist, prucalopride (500 micro g/kg, i.v), increased the firing activity (+35%) of 5-HT neurons displaying a high basal firing rate; subsequent injection of GR 125487 (500 micro g/kg, i.v.) suppressed this effect. These results indicate that 5-HT4 receptors exert both a tonic and a phasic, positive, frequency-related control on DRN 5-HT neuronal activity. The existence of such a control might open new avenues for therapeutic research in the antidepressant field.
Lucas
Guillaume
G
McGill University, Department of Psychiatry, Research and Training Building, Room 207, 1033 Avenue des Pins Ouest, Montréal, Québec, H3A 1A1, Canada.
Debonnel
Guy
G
D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D020117:Cisapride / Q000494:pharmacology; D004594:Electrophysiology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D062366:para-Aminobenzoates
D001572:Benzofurans; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D062366:para-Aminobenzoates; C406662:prucalopride; C072790:2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D010129:4-Aminobenzoic Acid; D020117:Cisapride; C082871:GR 113808