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 raphe 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.


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 microg/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-HT(4)-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.
Lucas
Guillaume
G
Département de Psychiatrie, Université McGill, Montréal, Québec, Canada.
Compan
Valérie
V
Charnay
Yves
Y
Neve
Rachael L
RL
Nestler
Eric J
EJ
Bockaert
Joël
J
Barrot
Michel
M
Debonnel
Guy
G
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D004594:Electrophysiology; D005110:Extracellular Space / Q000502:physiology; D005246:Feedback; D005625:Frontal Lobe / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000235:genetics; D017403:In Situ Hybridization; D007211:Indoles / Q000494:pharmacology; D007478:Iontophoresis; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D017966:Pyramidal Cells / Q000502:physiology; D015347:RNA Probes; D011903:Raphe Nuclei / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
D000814:Aniline Compounds; D001572:Benzofurans; D007211:Indoles; D010880:Piperidines; D015347:RNA Probes; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; C406662:prucalopride; D044422:Receptors, Serotonin, 5-HT4; C107826:RS 67333; D012701:Serotonin; C082871:GR 113808