Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT1A Receptor Biased Agonist

Sharon Cabanu,Adrian Newman-Tancredi,Albert Adell,Eva Florensa-Zanuy,Júlia Senserrich,Fuencisla Pilar-Cuéllar,Paula Zubakina

doi:10.3390/ph15030337

Abstract

Depression is the most prevalent of the mental illnesses and serotonin (5-hydroxytryptamine, 5-HT) is considered to be the major neurotransmitter involved in its etiology and treatment. In this context, 5-HT1A receptors have attracted interest as targets for therapeutic intervention. Notably the activation of presynaptic 5-HT1A autoreceptors delays antidepressant effects whereas the stimulation of postsynaptic 5-HT1A heteroreceptors is needed for an antidepressant action. NLX-101 (also known as F15599) is a selective biased agonist which exhibits preferred activation of cortical over brain stem 5-HT1A receptors. Here, we used behavioral, neurochemical and molecular methods to examine the antidepressant-like effects in rats of a single dose of NLX-101 (0.16 mg/kg, i.p.). NLX-101 reduced immobility in the forced swim test when measured 30 min but not 24 h after drug administration. NLX-101 increased extracellular concentrations of glutamate and dopamine in the medial prefrontal cortex, but no changes were detected in the efflux of noradrenaline or 5-HT. NLX-101 also produced an increase in the activation of pmTOR, pERK1/2 and pAkt, and the expression of PSD95 and GluA1, which may contribute to its rapid antidepressant action.

Highlights

The observation that ketamine, a widely used anesthetic drug, exerts a rapid antidepressant action within an hour of administration has been a breakthrough for the treatment of mood disorders [4,5]
We have studied the effects of the systemic administration of NLX-101 on the outflow of glutamate, noradrenaline, dopamine and
Our results showed, for the first time, that brain-derived neurotrophic factor (BDNF), pAkt and the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 are increased by a single systemic injection of NLX-101, with a time course which was slower compared with that of phospho–mammalian target of rapamycin (pmTOR) or phosphorylated extracellular-regulated kinase 1/2 (pERK1/2)

Summary

Introduction

Depression is a common mental disorder that affects approximately 300 million people worldwide. Even though the antidepressants elicit some therapeutic efficacy, they need to be taken for weeks or months before any meaningful clinical improvement emerges. More serious is the fact that approximately 30% of the patients have inadequate responses or no response at all to treatment [1–3]. In this context, the observation that ketamine, a widely used anesthetic drug, exerts a rapid antidepressant action within an hour of administration has been a breakthrough for the treatment of mood disorders [4,5]. Recent preclinical work has shown that the serotonin (5-hydroxytryptamine, 5-HT) system in the brain is involved in the sustained

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