The 5-HT1A receptor biased agonist, NLX-204, shows rapid-acting antidepressant-like properties and neurochemical changes in two mouse models of depression

Behav Brain Res. 2023 Feb 13;438:114207. doi: 10.1016/j.bbr.2022.114207. Epub 2022 Nov 8.


Activation of cortical serotonin 5-HT1A receptors may be a promising strategy to achieve rapid-acting antidepressant (RAAD) activity. NLX-204 is a selective 5-HT1A receptor biased agonist that, in naïve mice, robustly decreases immobility in the forced swim test (FST), and preferentially phosphorylates extracellular signal-regulated kinase (ERK1/2), involved in antidepressant activity. Here, we evaluated the properties of NLX-204 in two mouse models of depression. Male CD-1 mice were subjected to unpredictable chronic mild stress (UCMS) for 4-weeks or to repeated corticosterone (CORT, 20 mg/kg s.c./day) for 3-weeks before receiving acute administration of NLX-204 (2 mg/kg, p.o.). Depressive-like behavior was assessed in the FST, anhedonia-like behavior in the sucrose preference test (SPT) and locomotor activity was also recorded. Phosphorylation of ERK1/2 (pERK1/2) and cAMP response binding element (pCREB) were measured ex vivo in hippocampus and prefrontal cortex (PFC). UCMS or CORT treatment increased immobility in the FST, elicited a sucrose preference deficit, and decreased pERK1/2 and pCREB levels in PFC and hippocampus. NLX-204 reduced depressive-like behavior in the FST in CORT and UCMS mice, and normalized sucrose preference in CORT mice, suggesting anti-anhedonic activity. NLX-204 increased pERK1/2 levels in PFC of UCMS mice. NLX-204 also increased pCREB levels in PFC of CORT mice. These data suggest that NLX-204 has RAAD-like properties not only in naïve mice, but also in mice in a "depressive-like" state, and that these involve changes in PFC and hippocampal pERK1/2 and pCREB levels. These data provide additional evidence that activation of 5-HT1A receptors by selective biased agonists, such as NLX-204, may constitute a promising RAAD strategy.

Keywords: 5-HT(1A) receptors; Chronic mild stress; Creb; Depression; ERK1/2; NLX-204.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Depression* / drug therapy
  • Depression* / metabolism
  • Disease Models, Animal
  • Male
  • Mice
  • Receptor, Serotonin, 5-HT1A*
  • Serotonin / metabolism
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Sucrose


  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • Antidepressive Agents
  • Serotonin 5-HT1 Receptor Agonists
  • Sucrose