The peptidic antidepressant spadin interacts with prefrontal 5-HT(4) and mGluR(2) receptors in the control of serotonergic function.
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.
['Moha ou Maati|Hamid|H|', 'Bourcier-Lucas|Céline|C|', 'Veyssiere|Julie|J|', 'Kanzari|Ameni|A|', 'Heurteaux|Catherine|C|', 'Borsotto|Marc|M|', 'Haddjeri|Nasser|N|', 'Lucas|Guillaume|G|']
D000596:Amino Acids D000814:Aniline Compounds D000818:Animals D000928:Antidepressive Agents D002118:Calcium D065847:Dorsal Raphe Nucleus D051766:Early Growth Response Protein 1 D018691:Excitatory Amino Acid Antagonists D007211:Indoles D008297:Male D008810:Mice, Inbred C57BL D018345:Mice, Knockout D010455:Peptides D010879:Piperazines D010880:Piperidines D024683:Potassium Channels, Tandem Pore Domain D017397:Prefrontal Cortex D017207:Rats, Sprague-Dawley D018094:Receptors, Metabotropic Glutamate D044422:Receptors, Serotonin, 5-HT4 D059326:Serotonergic Neurons D058828:Serotonin 5-HT4 Receptor Agonists D017366:Serotonin Receptor Agonists D013449:Sulfonamides D014966:Xanthenes
Spadin Medial prefrontal cortex 5-HT neurons 5-HT4 receptors mGluR2/3 receptors 5-HT depolarization block