P.2.001 - Rapid anxiolytic effects of a serotonin type 4 receptor agonist involve prefrontal cortex/brainstem neural circuit recruitment

Abstract

Anxiety disorders are one of the most prevalent mental health conditions. Although benzodiazepines are very effective in reducing acute anxiety, their adverse effects limit their use chronically. Selective serotonin reuptake inhibitors (SSRIs) are considered to be the first line of therapy for anxiety disorders but their delayed onset of action emphasizes the need for faster acting drugs [1]. Recently, it has been suggested that 5-HT4 receptor (5-HT4R) may bring new hope for treating anxiety/depression symptoms [2]. This study aimed to assess whether acute 5-HT4R activation could induce fast-anxiolytic-like effects, using an anxious mouse strain. Thus, male BALB/cJRJ mice were administered intraperitoneally 45min before testing (open field, OF; elevated plus maze, EPM; novelty suppressed feeding, NSF) with a single dose of saline, fluoxetine (SSRI, 18 mg/kg), diazepam (benzodiazepine, 1.5 mg/kg) or RS67333 (5-HT4R agonist, 1.5 mg/kg). A one-way ANOVA followed by Fisher’s PLSD post-hoc test showed that, unlike fluoxetine, but similarly to diazepam, acute systemic RS67333 administration produced fast anxiolytic-like effect in all tested paradigms (i.e., +62% and +66% increase in time spent respectively in center in the OF and in the open arms in EPM and +63% reduce latency to feed in the NSF compared to vehicle, all p In addition, since the 5-HT4R is mainly expressed in the medial prefrontal cortex (mPFC) [3], we tested whether mPFC local injection, of RS6733 could mimic the anxiolytic effect of a systemic injection. Thus, a single dose of RS67333 (0.5 µg/side) administered in the mPFC 45 minutes prior testing showed comparable anxiolytic-like activity than that of the systemic diazepam (1.5 mg/kg) administration in the EPM and the NSF (i.e., + 77% increase in time spent in the open arms in the EPM compared to vehicle, all p Finally, we explored whether mPFC pyramidal cell projections-targeting to the dorsal raphe nucleus (DRN) circuit [4] is involved in RS67333 induced-anxiolytic-like activity. Interestingly, an acute mPFC injection of RS67333 and diazepam (1.5 µg/side) induced-fast anxiolytic-like effects was abolished in serotonin-pCPA depleted mice (-86% in the 5-HT content in the PFC of control mice) as compared to vehicle-treated mice (respectively, -78% and -73% less time spent in open arms in the EPM than vehicle-treated mice, all p In conclusion, our study demonstrated that (i) acute 5-HT4R activation induced fast anxiolytic-like effects in anxious stressed mice similar to benzodiazepine, (ii) the mPFC-DRN circuit contribute to the fast anxiolytic-like activity of RS67333 and diazepam and (iii) despite different pharmacological targets, 5-HT4R agonist and benzodiazepine, share common neural circuit recruitment to induced fast anxiolytic-like effect. Therefore, we envision that the 5-HT4R may represent an innovative and rapid onset therapeutic approach to treat anxiety disorders.