The 5-HT1A receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models

Two selective serotonin 5-HT1A 'biased' agonists, NLX-101 and NLX-204, produced rapid and sustained antidepressant-like effects in rats subjected to chronic mild stress, comparable to ketamine. In Wistar rats, both compounds dose-dependently reversed stress-induced reductions in sucrose consumption (a measure of anhedonia) from treatment day 1, with nearly full reversal by days 8 and 15, and effects persisting for three weeks after treatment stopped. They also improved working memory deficits and reduced anxiety-like behavior in the elevated plus maze. In Wistar-Kyoto rats, which are resistant to classical antidepressants, the compounds were also active, though less consistently. These findings suggest biased agonism at 5-HT1A receptors may offer a rapid-acting, sustained antidepressant strategy with additional benefits for memory and anxiety.

Study at a glance

Abstract

NLX-101 and NLX-204 are highly selective serotonin 5-HT1A ‘biased’ agonists, displaying potent and efficacious antidepressant-like activity upon acute administration in models such as the forced swim test. we compared the effects of repeated administration of NLX-101, NLX-204 and ketamine in the chronic mild stress (CMS) model of depression, considered to have high translational potential, on sucrose consumption (anhedonia measure), novel object recognition (NOR; working memory measure) and elevated plus maze (EPM; anxiety measure) in male Wistar and Wistar-Kyoto rats (the latter being resistant to classical antidepressants). in Wistar rats, NLX-204 and NLX-101 (0.08–0.16 mg/kg i.p.), like ketamine (10 mg/kg i.p.) dose-dependently reversed CMS-induced sucrose intake deficit from treatment Day 1, with nearly full reversal observed at the higher dose at Days 8 and 15. These effects persisted for 3 weeks following treatment cessation. In the NOR test, both doses of NLX-101/NLX-204, and ketamine, rescued the deficit in discrimination index caused by CMS on Days 3 and 17; all three compounds increased time spent in open arms (EPM) but only NLX-204 achieved statistical significance on Days 2 and 16. In Wistar-Kyoto rats, all 3 compounds were also active in the sucrose test and, to a lesser extent, in the NOR and EPM. In non-stressed rats (both strains), the three compounds produced no significant effects in all tests. these observations further strengthen the hypothesis that biased agonism at 5-HT1A receptors constitutes a promising strategy to achieve rapid-acting/sustained antidepressant effects combined with activity against TRD, in addition to providing beneficial effects against memory deficit and anxiety in depressed patients.