The 5-HT1A receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models
Psychopharmacology June 13, 2023 M. Papp, P. Gruca, M. Lason et al.
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.