5‐HT4 receptors exert a frequency‐related facilitatory control on dorsal raphé nucleus 5‐HT neuronal activity

Abstract

We investigated, using single‐unit recordings in chloral hydrate‐anaesthetized rats, the role of serotonin₄ (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 µg/kg, i.v.) or the selective 5‐HT₄ antagonist, GR 125487 (200– 2000 µg/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 µg/kg, respectively), an effect abolished by GR 125487 (500 µg/kg) and reduced by the 5‐HT₄ antagonist, SDZ 205557 (500 µg/kg, i.v). Conversely, GR 125487 induced a dose‐dependent inhibition of responders activity, which was almost completely suppressed at the dose of 2000 µg/kg. In a separate set of experiments, the selective 5‐HT₄ agonist, prucalopride (500 µg/kg, i.v), increased the firing activity (+35%) of 5‐HT neurons displaying a high basal firing rate; subsequent injection of GR 125487 (500 µg/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.