Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT 1A Receptor Biased AgonistMolecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT 1A Receptor Biased AgonistCabanu S, Pilar-Cuéllar F, Zubakina P, Florensa-Zanuy E, Senserrich J, Newman-Tancredi A, Adell A.2022-04-14T22:00:00Z<h3>​Abstract<br></h3><div><br></div><div><br></div><div>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.<br></div><p><a href="https://www.mdpi.com/1424-8247/15/3/337">Pharmaceuticals (Basel)</a>. 2022 Mar 10;15(3):337.<br></p>403