The 5-HT_1A receptor biased agonist, NLX-204, shows rapid-acting antidepressant-like properties and neurochemical changes in two mouse models of depression

The takeaway

A single oral dose of the biased 5-HT_1A agonist NLX-204 reverses behavioral deficits and normalizes plasticity-related signaling across two mouse depression models.

The science

In unpredictable chronic mild stress and chronic corticosterone models, NLX-204 reversed anhedonia and passive stress coping without affecting locomotion. This compound also restored key intracellular markers of neuroplasticity (increases in pERK1/2 and pCREB) in the hippocampus and prefrontal cortex. The consistent effects across both depression models improve construct validity and translational relevance.

Why it matters

Biased 5-HT_1A receptor activation demonstrates rapid-acting, ketamine-like antidepressant potential while directly engaging cortical plasticity pathways-supporting 5-HT_1A-targeted strategies as a promising approach for mechanism-based antidepressant development.

Original article

https://doi.org/10.1016/j.bbr.2022.114207