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

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.

NLX-101, a 5-HT1A receptor-biased agonist, improves pattern separation and stimulates neuroplasticity in aged rats

“…Reductions of synaptophysin and PSD-95 protein levels as well as neurogenesis have been observed in aged animals and have been implicated in learning and memory deficits ( van Guilder et al, 2011 ). Upon acute administration, NLX-101 transiently increases PSD-95 levels in the cortex of younger rats ( Cabanu et al, 2022 ). Here, we observed that NLX-101 increased the hippocampal levels of PSD-95 and concomitantly ameliorated OPS performance in aged animals, indicating cognitive improvement.…”

“…In several interaction studies, the effects of NLX-101 were antagonized by the 5-HT 1A antagonist WAY100635, indicating specificity of receptor targeting ( Assié et al, 2006 ;Lladó-Pelfort et al, 2010 ;. NLX-101 preferentially activates postsynaptic 5-HT 1A receptors at doses that do not inhibit dorsal raphe neuron firing or serotonin release and its effects have been related to its potency for G αiprotein activation, adenylyl cyclase inhibition, and ERK1/2 phosphorylation ( Cabanu et al, 2022 ;Newman-Tancredi et al, 2009 ). It should be noted, however, that 5-HT 1A receptors preferentially couple to G αi in the cerebral cortex but not in the hippocampus ( Mannoury la Cour et al, 2006 ), suggesting brain region differences in the effects of NLX-101.…”

“…Aging-induced cognitive dysfunction has been associated with decreased levels of BDNF in the hippocampus ( Belviranli, Okudan, 2018 ;Erickson et al, 2010 ;Luellen et al, 2007 ), whereas activities that increase BDNF levels, for example, physical exercise, may upregulate BDNF expression and counteract age-related cognitive deficits ( Cotman et al, 2007 ;Vivar et al, 2013 ). NLX-101 has previously been shown to elicit rapid increases in cortical BDNF levels within 2 hours following acute administration ( Cabanu et al, 2022 ) and following 2-week administration in hippocampi of younger rats ( van Hagen et al, 2022 ). Moreover, BDNF in the hippocampus, in particular in the DG, has been proposed to play an important role in pattern separation tasks.…”

Deciphering Ketamine’s Dual Outcomes: Distinguishing Psychotic from Antidepressant Effects, and Their Temporal Dynamics in Mice

“…Thirty-six animals were used (6 per group/time). Western Blot analysis was performed according to the protocol previously employed (30) to quantify Akt, ERK, mTOR (and its phosphorylated forms), and PSD95. The primary antibodies used were: mouse anti- Ecuphar, Barcelona, Spain; 0.8 -1 l/min O2) and positioned in a stereotaxic frame (Narishige, Japan).…”

Sigma-1 Receptors in Depression: Mechanism and Therapeutic Development

“…CaMKIV/II is an intracellular Ca 2+ -sensitive sensor. High concentrations of Ca 2+ activate CaMK IV/II, and then eventually activate (phosphorylate) intermediates in the ERK1/2 and mTOR pathways ( Cabanu et al, 2022 ), thus inducing a rapid synthesis of PSD95 as well as facilitating the phosphorylation of CREB, thus boosting the expression of BDNF involved in neuroplasticity ( Fukunaga and Moriguchi, 2017 ) ( Figure 1 ). Moriguchi et al ( Moriguchi et al, 2015 ) used a CaMK deficiency strategy in vivo to reveal that the mechanism of antidepressant action of sigma-1 receptors may be due to regulation of the intracellular Ca 2+ level and activation of an alternative CaMKII-dependent mechanism for controlling the expression of BDNF.…”