NLX-101, a highly selective 5-HT1A receptor biased agonist, mediates antidepressant-like activity in rats via prefrontal cortex 5-HT1A receptors

NLX-101 (also known as F15599) exhibits nanomolar affinity, exceptional selectivity and biased agonist activation of serotonin 5-HT1A receptors. Given systemically, it displays antidepressant-like activity in the rat forced swim test (FST), and preferentially activates 5-HT1A post-synaptic hetemreceptors in the prefrontal cortex (PFC), a brain region involved in the control of mood. Here, we assessed the ability of NLX-101 to produce antidepressant-like activity in the FST following in-situ PFC unilateral microinjection. (+)8-OH-DPAT and F13714, two 5-HT1A receptor agonists that do not display cortical biased agonism, were tested as comparators. NLX-101 decreased time spent in immobility in a bi-modal manner, with a first MED of 0.25 mu g (immobility reduced from 160 to 80 s) but immobility returned to control levels at the next dose (1 mu g). At higher doses, immobility decreased monotonically, with a second MED of 16 mu g and a maximal effect (36 s) at 32 mu g. (+)8-OH-DPAT and F13714 also diminished immobility but, unlike NLX-101, they did so in a unimodal manner, with MEDs of 1 and 4 mu g, and maximal responses of 31 and 4 s, for (+)8-OH-DPAT and F13714, respectively. The effects of (+)8-OH-DPAT (16 jig) and of both active doses of NLX-101 (0.25 and 16 mu g) were prevented by the 5-HT1A receptor antagonist WAY-100,635 (0.63 mg/kg s.c.). In conclusion, activation of 5-HT1A receptors in the PFC by NLX-101 produces robust antidepressant-like effects in the rat FST, with a distinctive bimodal dose-response pattern. These data suggest that NLX-101 may target specific 5-HT1A receptor subpopulations in PFC, likely located on GABAergic and/or glutamatergic neurons.

Automated summary

NLX-101 activates 5-HT1A receptors in the prefrontal cortex of rats, producing robust antidepressant-like effects with a distinctive bimodal dose-response pattern. These data suggest NLX-101 may target specific subpopulations of 5-HT1A receptors in the PFC, likely located on GABAergic and/or glutamatergic neurons.