Frontocortical 5-HT₄ receptors exert positive feedback on serotonergic activity: Viral transfections, subacute and chronic treatments with 5-HT₄ agonists

Background: We recently identified a facilitory control exerted by serotonin₄ (5-HT₄) receptors on the in vivo firing activity of dorsal raphé nucleus (DRN) serotonergic (5-HT) neurons. However, these findings were based on acute administrations of 5-HT₄ receptor agonists and antagonists, which were active only in a subpopulation of 5-HT neurons. We had no evidence that this influence was significant when considering the entire DRN, nor if it was persistent after chronic treatments. In addition, the poor distribution of 5-HT₄ receptors within the DRN raised the question of the neuroanatomical bases underlying this control. Methods and Results: Here we show that the subacute intraperitoneal (IP) injection of the 5-HT₄ receptor agonists prucalopride (2.5 mg/kg) and RS 67333 (1.5 mg/kg) 30 minutes before the beginning of recordings augment the mean firing rate of DRN neurons by 40% and 66%, respectively. These increases remain stable when the compounds are administered continuously during 3 and 21 days; the effects of the 3-day treatment are blocked by the 5-HT₄ receptor antagonist GR 125487 (1000 μg/kg, intravenous [i.v.]). In addition, stereotaxic microinjections of herpes simplex viruses, transformed to overexpress 5-HT₄ receptors, increase DRN 5-HT neuronal mean activity when performed in the medial prefrontal cortex (mPFC) but not in the striatum or in the hippocampus. Conclusions: This finding suggests the existence of a 5-HT₄-dependent activation of DRN that may involve the mPFC, unveiling the 5-HT₄ receptor as a putative player in the physiopathology of several disorders related to central 5-HT dysfunction.