2024/08/27 by Faranak Vahid-Ansari, Adrian Newman-Tancredi, Adrian Newman‐Tancredi +3 · 1 citation
Neuroscience · Medicine · #Tryptophan and brain disorders #Treatment of Major Depression #Neuroscience and Neuropharmacology Research
paper · doi:10.1016/j.neuropharm.2024.110132
Selective serotonin (5-HT) reuptake inhibitors (SSRIs) like fluoxetine remain a first-line treatment for major depression, but are effective in less than half of patients and can take 4–8 weeks to show results. In this study, we examined cF1ko mice with genetically induced upregulation of 5-HT1A autoreceptors that reduces 5-HT neuronal activity. These mice display anxiety- and depression-related behaviors that did not respond to chronic fluoxetine treatment. We examined treatment with NLX-101, a biased agonist that preferentially targets 5-HT1A heteroreceptors. By testing different doses of NLX-101, we found that a dose of 0.2 mg/kg was effective in reducing depression-related behavior in cF1ko mice without causing hypothermia, a 5-HT1A autoreceptor-mediated response. After 1 h, this dose activated dorsal raphe 5-HT neurons and cells in the medial prefrontal cortex (mPFC), increasing nuclear c-fos labelling in cF1ko mice. In cF1ko mice but not wild-type littermates, 0.2 mg/kg NLX-101 administered 1 h prior to each behavioral test for two weeks reduced depressive behavior in the forced swim test, but increased anxiety-related behaviors in the open field, elevated plus maze, and novelty suppressed feeding tests. During this treatment, NLX-101 induced widespread increases in the density of 5-HT axons, varicosities, and especially synaptic and triadic structures, particularly in depression-related brain regions including mPFC, hippocampal CA1 and CA2/3, amygdala and nucleus accumbens of cF1ko mice. Overall, NLX-101 was rapid and effective in reducing depressive behavior in SSRI-resistant mice, but also induced anxiety-related behaviors. The increase in serotonin innervation induced by intermittent NLX-101 may contribute to its behavioral actions. • The cF1ko mouse with lower serotonin activity modeled SSRI resistant depression. • Acutely, the 5-HT1A heteroreceptor biased agonist NLX-101 activated serotonin neurons. • Repeated NLX-101 treatment reduced depressive behavior but increased anxiety. • Repeated NLX-101 induced widespread serotonin innervation within two weeks. • By increasing serotonin activity NLX-101 may be effective in SSRI resistant depression.