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The peptidic antidepressant spadin interacts with prefrontal 5-HT4 and mGluR2 receptors in the control of serotonergic function

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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 Ca2+ 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.

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Acknowledgments

This study was funded by grants from the Agence Nationale de la Recherche (ANR-2009-MNPS-026.01 and ANR EMMA 11-050), as well as by financial supports from the INSERM, the CNRS, the Université de Nice-Sophia Antipolis, and the LabEx Ionic Channels Science and Therapeutics (ICST, ANR-11 LABX 0015).

Conflict of interest

Doctors Heurteaux and Borsotto have patented the use of spadin as a putative antidepressant. The other authors reported no biomedical financial interests or potential conflicts of interest.

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  1. Guillaume Lucas

    Present address: INSERM U 862, Neurocentre Magendie, 146 rue Léo Saignat, 33077, Bordeaux Cedex, France

Authors and Affiliations

  1. Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-Université de Nice Sophia Antipolis, Valbonne, France

    Hamid Moha ou Maati, Julie Veyssiere, Ameni Kanzari, Catherine Heurteaux & Marc Borsotto

  2. INSERM U 846, Stem cell and Brain Research Institute, Université Lyon 1, Lyon, France

    Céline Bourcier-Lucas, Nasser Haddjeri & Guillaume Lucas

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  1. Hamid Moha ou Maati
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  2. Céline Bourcier-Lucas
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  3. Julie Veyssiere
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  4. Ameni Kanzari
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  5. Catherine Heurteaux
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  8. Guillaume Lucas
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Correspondence to Guillaume Lucas.

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H. Moha ou Maati and C. Bourcier-Lucas contributed equally to this work.

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Moha ou Maati, H., Bourcier-Lucas, C., Veyssiere, J. et al. The peptidic antidepressant spadin interacts with prefrontal 5-HT4 and mGluR2 receptors in the control of serotonergic function. Brain Struct Funct 221, 21–37 (2016). https://doi.org/10.1007/s00429-014-0890-x

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