Biased 5-HT1A agonist NLX-101 improves executive function under NMDA receptor hypofunction and preferentially enhances cortical ERK2 phosphorylation

Abstract

Cognitive inflexibility and working memory deficits are major contributors to functional impairment in neuropsychiatric disorders and remain insufficiently addressed by current treatments. NLX-101, a preferential postsynaptic 5-HT_1A receptor biased agonist, engages cortical serotonergic signaling and ERK1/2-related pathways, offering a mechanistically distinct approach to improving prefrontal cortex-dependent cognition. Here, we examined whether NLX-101 counteracts executive function deficits induced by NMDA receptor blockade in BALB/c mice. Working memory was assessed using the 8-arm radial maze, whereas cognitive flexibility was evaluated in a touchscreen-based visual discrimination/reversal learning task. Repeated oral administration of NLX-101 improved MK-801-induced working memory deficits and enhanced reversal learning performance, particularly during the later phase of contingency updating. These behavioral effects were accompanied by preferential enhancement of ERK2 phosphorylation in the prefrontal cortex, consistent with the biased signaling profile of NLX-101. In the touchscreen task, NLX-101 produced clearer improvement than vortioxetine under the dosing and timing conditions used here. Together, these findings identify NLX-101 as a promising pharmacological tool for improving executive dysfunction associated with impaired glutamatergic transmission and support further investigation of biased cortical 5-HT_1A receptor signaling as a therapeutic strategy for cognitive symptoms in neuropsychiatric disorders.