title: The peptidic antidepressant spadin interacts with prefrontal 5-HT(4) and mGluR(2) receptors in the control of serotonergic function.
abstract: This study investigates the mechanism of action of spadin, a putative fast-acting peptidic antidepressant (AD) and a functional blocker of the K(+) TREK-1 channel, in relation with the medial prefrontal cortex (mPFC)-dorsal raphé (DRN) serotonergic (5-HT) neurons connectivity. Spadin increased 5-HT neuron firing rate by 113%, an augmentation abolished after electrolytic lesion of the mPFC. Among the few receptor subtypes known to modulate TREK-1, the stimulation of 5-HT4 receptors and the blockade of mGluR2/3 ones both activated 5-HT impulse flow, effects also suppressed by mPFC lesion. The combination of spadin with the 5-HT4 agonist RS 67333 paradoxically reduced 5-HT firing, an effect reversed by acutely administering the 5-HT1A agonist flesinoxan. It also had a robust synergetic effect on the expression of Zif268 within the DRN. Together, these results strongly suggest that 5-HT neurons underwent a state of depolarization block, and that the mechanisms underlying the influences exerted by spadin and RS 67333 are additive and independent from each other. In contrast, the mGluR2/3 antagonist LY 341495 occluded the effect of spadin, showing that it likely depends on mPFC TREK-1 channels coupled to mGluR2/3 receptors. These in vivo electrophysiological data were confirmed by in vitro Ca(2+) cell imaging performed in cultured cortical neurons. Altogether, our results indicate that spadin, as a natural compound, constitutes a very good candidate to explore the "glutamatergic path" of fast-acting AD research. In addition, they provide the first evidence of 5-HT depolarization block, showing that the combination of 5-HT activators for strategies of AD augmentation should be performed with extreme caution.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Hamid
authors.initials: H
authors.lastname: Moha ou Maati
authors.affiliation: INSERM U 846, Stem cell and Brain Research Institute, Université Lyon 1, Lyon, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Bourcier-Lucas
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Veyssiere
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Ameni
authors.initials: A
authors.lastname: Kanzari
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Heurteaux
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Borsotto
authors.affiliation: INSERM U 846, Stem cell and Brain Research Institute, Université Lyon 1, Lyon, France.
authors.forename: Nasser
authors.initials: N
authors.lastname: Haddjeri
authors.affiliation: INSERM U 846, Stem cell and Brain Research Institute, Université Lyon 1, Lyon, France. guillaume.lucas@inserm.fr.|INSERM U 862, Neurocentre Magendie, 146 rue Léo Saignat, 33077, Bordeaux Cedex, France. guillaume.lucas@inserm.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lucas
mesh_terms: D000596:Amino Acids / Q000008:administration & dosage; D000814:Aniline Compounds / Q000008:administration & dosage; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D002118:Calcium / Q000378:metabolism; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors / Q000235:genetics; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology*; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000502:physiology*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000008:administration & dosage; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D014966:Xanthenes / Q000008:administration & dosage
chemical_list: D000596:Amino Acids; D000814:Aniline Compounds; D000928:Antidepressive Agents; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; C114624:LY 341495; D010455:Peptides; D010879:Piperazines; D010880:Piperidines; D024683:Potassium Channels, Tandem Pore Domain; D018094:Receptors, Metabotropic Glutamate; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C103742:potassium channel protein TREK-1; C551795:spadin peptide; D044422:Receptors, Serotonin, 5-HT4; C107826:RS 67333; C056895:flesinoxan; D002118:Calcium; C082871:GR 113808
keywords: 5-HT depolarization block; 5-HT neurons; 5-HT4 receptors; Medial prefrontal cortex; Spadin; mGluR2/3 receptors