Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT<sub>1A</sub> Receptor Biased Agonist
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-HT<sub>1A</sub> receptors have attracted interest as targets for therapeutic interv...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/3/337 |
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| author | Sharon Cabanu Fuencisla Pilar-Cuéllar Paula Zubakina Eva Florensa-Zanuy Júlia Senserrich Adrian Newman-Tancredi Albert Adell |
| author_facet | Sharon Cabanu Fuencisla Pilar-Cuéllar Paula Zubakina Eva Florensa-Zanuy Júlia Senserrich Adrian Newman-Tancredi Albert Adell |
| author_sort | Sharon Cabanu |
| collection | DOAJ |
| description | 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-HT<sub>1A</sub> receptors have attracted interest as targets for therapeutic intervention. Notably the activation of presynaptic 5-HT<sub>1A</sub> autoreceptors delays antidepressant effects whereas the stimulation of postsynaptic 5-HT<sub>1A</sub> 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-HT<sub>1A</sub> 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. |
| first_indexed | 2024-03-09T13:00:42Z |
| format | Article |
| id | doaj.art-57a3290157564379bb93367a54345fe3 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T13:00:42Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-57a3290157564379bb93367a54345fe32023-11-30T21:54:42ZengMDPI AGPharmaceuticals1424-82472022-03-0115333710.3390/ph15030337Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT<sub>1A</sub> Receptor Biased AgonistSharon Cabanu0Fuencisla Pilar-Cuéllar1Paula Zubakina2Eva Florensa-Zanuy3Júlia Senserrich4Adrian Newman-Tancredi5Albert Adell6Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria, 39011 Santander, SpainInstituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria, 39011 Santander, SpainInstituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria, 39011 Santander, SpainInstituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria, 39011 Santander, SpainInstituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria, 39011 Santander, SpainNeurolixis SAS, 2 Rue Georges Charpak, 81100 Castres, FranceInstituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria, 39011 Santander, SpainDepression 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-HT<sub>1A</sub> receptors have attracted interest as targets for therapeutic intervention. Notably the activation of presynaptic 5-HT<sub>1A</sub> autoreceptors delays antidepressant effects whereas the stimulation of postsynaptic 5-HT<sub>1A</sub> 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-HT<sub>1A</sub> 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.https://www.mdpi.com/1424-8247/15/3/337mTORERK1/2GluA1p11BDNFAkt |
| spellingShingle | Sharon Cabanu Fuencisla Pilar-Cuéllar Paula Zubakina Eva Florensa-Zanuy Júlia Senserrich Adrian Newman-Tancredi Albert Adell Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT<sub>1A</sub> Receptor Biased Agonist Pharmaceuticals mTOR ERK1/2 GluA1 p11 BDNF Akt |
| title | Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT<sub>1A</sub> Receptor Biased Agonist |
| title_full | Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT<sub>1A</sub> Receptor Biased Agonist |
| title_fullStr | Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT<sub>1A</sub> Receptor Biased Agonist |
| title_full_unstemmed | Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT<sub>1A</sub> Receptor Biased Agonist |
| title_short | Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT<sub>1A</sub> Receptor Biased Agonist |
| title_sort | molecular signaling mechanisms for the antidepressant effects of nlx 101 a selective cortical 5 ht sub 1a sub receptor biased agonist |
| topic | mTOR ERK1/2 GluA1 p11 BDNF Akt |
| url | https://www.mdpi.com/1424-8247/15/3/337 |
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