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 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.

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

“…The fast onset of action of the 5-HT 4 receptor agonist could be a consequence of an increase in serotonergic output to projection areas (Lucas et al, 2005;Lucas and Debonnel, 2002). Indeed, by measuring spontaneous electrical activity in mice lacking 5-HT 4 receptors, Conductier et al (2006) demonstrated that 5-HT 4 receptors exert a tonic positive influence on the firing activity of dorsal raphe nucleus 5-HT neurons, and previous studies have shown that 5-HT 4 receptor activation by selective agonists modulates central 5-HT neurotransmission, increasing the firing of dorsal raphe nucleus 5-HT neurons (Lucas and Debonnel, 2002).…”

“…Indeed, by measuring spontaneous electrical activity in mice lacking 5-HT 4 receptors, Conductier et al (2006) demonstrated that 5-HT 4 receptors exert a tonic positive influence on the firing activity of dorsal raphe nucleus 5-HT neurons, and previous studies have shown that 5-HT 4 receptor activation by selective agonists modulates central 5-HT neurotransmission, increasing the firing of dorsal raphe nucleus 5-HT neurons (Lucas and Debonnel, 2002). There is also accumulating evidence that cortical regions are involved in 5-HT4-induced anxiolytic/antidepressant-like activities (Lucas et al, 2005) (for review see also (Lucas, 2009)).…”

“…It has been proposed that 5-HT 4 receptor agonists such as RS67333 may bring new hope for treating depression (Lucas, 2009;Lucas et al, 2005;Lucas and Debonnel, 2002;Lucas et al, 2010;Lucas et al, 2007). Indeed, administration of 5-HT 4 agonists induced similar molecular and behavioral changes as common antidepressants in rodents (Bockaert et al, 2008;Lucas et al, 2007;Pascual-Brazo et al, 2012).…”

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…Both 5-HT4-Rs and 5-HT5A-Rs have been shown to exert negative feedback control over the DRN, probably via an indirect, mPFC-mediated, and a direct, autoreceptor-mediated, mechanism respectively (Lucas et al, 2005;Lucas and Debonnel, 2002;Thomas et al, 2006). Genetic deletion of the mouse Htr5a has minimal effect on anxiety-like behavior .…”

Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation

“…Interestingly, 5-HT 4 Rs exert both a tonic and a phasic stimulatory control over dorsal 5-HT raphe neurons (Lucas and Debonnel 2002). This effect might be enhanced by the activation of 5-HT 4 Rs expressed in the medial prefrontal cortex (Lucas et al 2005).…”