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

NLX-101 (also known as F15599) exhibits nanomolar affinity, exceptional selectivity and biased agonist activation of serotonin 5-HT receptors. Given systemically, it displays antidepressant-like activity in the rat forced swim test (FST), and preferentially activates 5-HT post-synaptic heteroreceptors 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-HT 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 μg (immobility reduced from 160 to 80 s) but immobility returned to control levels at the next dose (1 μg). At higher doses, immobility decreased monotonically, with a second MED of 16 μg and a maximal effect (36 s) at 32 μg. (+)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 μg, and maximal responses of 31 and 4 s, for (+)8-OH-DPAT and F13714, respectively. The effects of (+)8-OH-DPAT (16 μg) and of both active doses of NLX-101 (0.25 and 16 μg) were prevented by the 5-HT receptor antagonist WAY-100,635 (0.63 mg/kg s.c.). In conclusion, activation of 5-HT 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-HT receptor subpopulations in PFC, likely located on GABAergic and/or glutamatergic neurons.