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Rôle du récepteur sérotoninergique de type 4 dans le traitement rapide et prophylactique de l’anxiété : implication du circuit cortex-raphé

Abstract : Benzodiazepines (BZD) and antidepressants are effective in reducing anxiety, but adverse effects of BZD and the delayed onset of action of antidepressants emphasize the need to develop fast-acting new drugs. Recent studies indicated that activation of 5-HT4 receptor (5-HT4R) could be a promising target. Although a number of studies have assessed 5-HT4R agonist anxiolytic activity after chronic treatment, few of them have neither evaluated their anxiolytic profile acutely, neither the brain circuits involved in this behavioral activity. Here, we evaluated whether acute 5-HT4R activation in glutamatergic axon terminals arising from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN), a circuit involved in emotional processes, induced fast anxiolytic effects, using pharmacologic, electrophysiologic and optogenetic tools. Acute systemic administration and intra-mPFC infusion of 5-HT4R produced fast anxiolytic effects in mice and increased DRN serotonin cell firing. Optogenetically activating mPFC terminals targeting the DRN reduced anxiety in mice whereas silencing this circuit blocked BZD (diazepam) and 5-HT4R agonist (RS 67333) mPFC infusion -induced anxiolytic effects. However, anxiolytic effects induced by an acute systemic administration of both molecules were partially blocked after optogenetically inhibiting cortical glutamatergic terminals in the DRN, suggesting that cortex-brainstem neural circuit is necessary but not sufficient for a rapid activity of diazepam and RS 67333. Finally, the prophylactic administration of a 5-HT4R agonist before stress prevented the development of an anxio-depressive phenotype in mice, suggesting that this molecule could reinforce the resilience of population at risk.
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Charlène Faye. Rôle du récepteur sérotoninergique de type 4 dans le traitement rapide et prophylactique de l’anxiété : implication du circuit cortex-raphé. Pharmacologie. Université Paris Saclay (COmUE), 2019. Français. ⟨NNT : 2019SACLS090⟩. ⟨tel-02682432v2⟩

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