Cortical 5-hydroxytryptamine 1A receptor biased agonist, NLX-101, displays rapid-acting antidepressant-like properties in the rat chronic mild stress model

Abstract

Background: NLX-101 (also known as F15599) is a highly selective and efficacious ‘biased’ agonist at cortical 5-hydroxytryptamine 1A (5-HT1A) heteroreceptors. In rodents, it possesses marked antidepressant-like activity, potently and completely abolishing immobility in the forced swim test (FST) with extended duration of action. Methods: We investigated the antidepressant-like activity of NLX-101 using the rat chronic mild stress (CMS) model of depression, considered to have a higher translational potential than the FST, as it possesses construct, face and predictive validity. The effects of CMS and repeated NLX-101 treatment were tested using sucrose consumption (a measure of anhedonia), novel object recognition (NOR; a measure of working memory) and elevated plus maze (EPM; a measure of anxiety) tests. Results: NLX-101 reversed the CMS-induced decrease of sucrose intake on day 1 of testing, with full reversal observed at the dose of 0.16 mg/kg and a less pronounced but still significant effect at 0.04 mg/kg, both given twice a day intraperitoneally. The effects of NLX-101 were maintained over the 2 week treatment period and persisted for four weeks following cessation of treatment. In the NOR test, both doses of NLX-101 rescued the deficit in discrimination index caused by CMS, without any effect on locomotor activity. However, NLX-101 had no effect on the reduction of open-arms entries produced by CMS in the EPM model. In control, non-stressed rats, NLX-101 produced non-significant effects in all three models. Conclusions: NLX-101 displayed efficacious activity in the CMS test, with more rapid (1 day) antidepressant-like effects than pharmacological compounds tested previously under the same experimental conditions. These observations suggest that biased agonist targeting of cortical 5-HT1A receptors constitutes a promising strategy to achieve rapid-acting and sustained antidepressant effects.

The selective 5-HT1A receptor biased agonists, F15599 and F13714, show antidepressant-like properties after a single administration in the mouse model of unpredictable chronic mild stress

“…Moreover, we administered the compounds acutely as we intended to show similarities between the studied biased 5-HT 1A agonists and rapid-acting ketamine. However, considering that neither F15599 nor F13714 reversed the stressed mice's anhedoniclike behavior in the SPT and based on studies in rats (Depoortère et al 2019), we may speculate that the compounds need to be administered at least twice or chronically. This issue will require future studies.…”

“…The agonists did not, however, reverse the anhedonic-like deficit in the sucrose preference test in the stressed mice, unlike ketamine. As a comparison, a recent study in rats by Depoortère et al (2019) showed that F15599, administered ip twice daily, reversed the chronic mild stress-induced decrease in sucrose intake. This was observed from day 1 of testing and was maintained throughout the 2 weeks of treatment and up to 4 weeks after cessation of treatment.…”

“…However, induction of serotonin syndrome, typified by flat body posture, forepaw treading, and lower lip retraction, was seen especially in the case of F13714 for which these effects were significantly more pronounced (Jastrzębska-Więsek et al 2018). Recently, a rapid-onset antidepressant-like activity of F15599 was observed in rats subjected to unpredictable chronic mild stress (UCMS) procedure, a robust animal model of depression (Depoortère et al 2019). Moreover, besides its mood-related properties, F15599 also improved animals' cognitive performance in the novel object recognition test (Depoortère et al 2019) and novel object pattern separation task (Van Goethem et al 2015), and reversed the memory impairment caused by phencyclidine (Depoortère et al 2010;Horiguchi and Meltzer 2012), unlike F13714.…”

“…Recently, a rapid-onset antidepressant-like activity of F15599 was observed in rats subjected to unpredictable chronic mild stress (UCMS) procedure, a robust animal model of depression (Depoortère et al 2019). Moreover, besides its mood-related properties, F15599 also improved animals' cognitive performance in the novel object recognition test (Depoortère et al 2019) and novel object pattern separation task (Van Goethem et al 2015), and reversed the memory impairment caused by phencyclidine (Depoortère et al 2010;Horiguchi and Meltzer 2012), unlike F13714. The broad scope of pharmacological properties of 5-HT 1A receptor biased agonists therefore encourages further investigation of their effects in diverse models and across different species.…”

Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT1A Receptor Biased Agonist

“…Recent preclinical studies have demonstrated that the administration of the highly selective 5-HT 1A receptor biased agonist, NLX-101 (also known as F15599), results in a rapid antidepressant-like response, both in naïve animals [ 12 , 13 ] and rodent models of depression [ 14 , 15 ], presumably through the activation of cortical 5-HT 1A receptors. Indeed, direct cortical microinjection of NLX-101 reduced immobility in the forced swim test, an effect that was blocked by the selective 5-HT 1A receptor antagonist, WAY-100635 [ 16 ].…”