Two compounds that selectively activate serotonin 5-HT1A receptors in a biased manner, NLX-101 and NLX-204, produce rapid antidepressant effects in rats exposed to chronic mild stress, similar to ketamine. When injected directly into the prefrontal cortex, these compounds reversed stress-induced anhedonia, reduced anxiety, and improved working memory deficits. Blocking 5-HT1A receptors in the prefrontal cortex eliminated these benefits, showing that the compounds work specifically through these receptors. The findings suggest that biased agonism at 5-HT1A receptors is a promising strategy for rapid-acting antidepressants that may avoid ketamine's side effects while also addressing cognitive deficits and anxiety.
Ketamine rapidly reverses depression-like symptoms in rats exposed to chronic mild stress, including loss of pleasure and working memory deficits, when given systemically or directly into the prefrontal cortex. Blocking serotonin 5-HT1A receptors in the prefrontal cortex with WAY-100635 prevents these effects, showing that ketamine's rapid antidepressant and pro-cognitive actions require activation of these receptors. The findings suggest that drugs directly targeting prefrontal cortex 5-HT1A receptors could provide rapid antidepressant effects and improve cognitive deficits without ketamine's side effects or need for clinical supervision.