Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects.
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| Title: | Selective siRNA-mediated suppression of 5-HT |
|---|---|
| Authors: | Bortolozzi, A, Castañé, A, Semakova, J, Santana, N, Alvarado, G, Cortés, R, Ferrés-Coy, A, Fernández, G, Carmona, M C, Toth, M, Perales, J C, Montefeltro, A, Artigas, F |
| Source: | Molecular Psychiatry. Jun2012, Vol. 17 Issue 6, p612-623. 12p. |
| Subjects: | Mental depression, Serotonin uptake inhibitors, Autoreceptors, Antidepressants, Genetic polymorphisms |
| Abstract: | Depression is a major health problem worldwide. Most prescribed anti-depressants, the selective serotonin reuptake inhibitors (SSRI) show limited efficacy and delayed onset of action, partly due to the activation of somatodendritic 5-HT1A-autoreceptors by the excess extracellular serotonin (5-HT) produced by SSRI in the raphe nuclei. Likewise, 5-HT1A receptor (5-HT1AR) gene polymorphisms leading to high 5-HT1A-autoreceptor expression increase depression susceptibility and decrease treatment response. In this study, we report on a new treatment strategy based on the administration of small-interfering RNA (siRNA) to acutely suppress 5-HT1A-autoreceptor-mediated negative feedback mechanisms. We developed a conjugated siRNA (C-1A-siRNA) by covalently binding siRNA targeting 5-HT1A receptor mRNA with the SSRI sertraline in order to concentrate it in serotonin axons, rich in serotonin transporter (SERT) sites. The intracerebroventricular (i.c.v.) infusion of C-1A-siRNA to mice resulted in its selective accumulation in serotonin neurons. This evoked marked anti-depressant-like effects in the forced swim and tail suspension tests, but did not affect anxiety-like behaviors in the elevated plus-maze. In parallel, C-1A-siRNA administration markedly decreased 5-HT1A-autoreceptor expression and suppressed 8-OH-DPAT-induced hypothermia (a pre-synaptic 5-HT1AR effect in mice) without affecting post-synaptic 5-HT1AR expression in hippocampus and prefrontal cortex. Moreover, i.c.v. C-1A-siRNA infusion augmented the increase in extracellular serotonin evoked by fluoxetine in prefrontal cortex to the level seen in 5-HT1AR knockout mice. Interestingly, intranasal C-1A-siRNA administration produced the same effects, thus opening the way to the therapeutic use of C-1A-siRNA. Hence, C-1A-siRNA represents a new approach to treat mood disorders as monotherapy or in combination with SSRI. [ABSTRACT FROM AUTHOR] |
| Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
| FullText | Links: – Type: pdflink Text: Availability: 0 |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 75394612 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Selective siRNA-mediated suppression of 5-HT<subscript>1A</subscript> autoreceptors evokes strong anti-depressant-like effects. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Bortolozzi%2C+A%22">Bortolozzi, A</searchLink><br /><searchLink fieldCode="AR" term="%22Castañé%2C+A%22">Castañé, A</searchLink><br /><searchLink fieldCode="AR" term="%22Semakova%2C+J%22">Semakova, J</searchLink><br /><searchLink fieldCode="AR" term="%22Santana%2C+N%22">Santana, N</searchLink><br /><searchLink fieldCode="AR" term="%22Alvarado%2C+G%22">Alvarado, G</searchLink><br /><searchLink fieldCode="AR" term="%22Cortés%2C+R%22">Cortés, R</searchLink><br /><searchLink fieldCode="AR" term="%22Ferrés-Coy%2C+A%22">Ferrés-Coy, A</searchLink><br /><searchLink fieldCode="AR" term="%22Fernández%2C+G%22">Fernández, G</searchLink><br /><searchLink fieldCode="AR" term="%22Carmona%2C+M+C%22">Carmona, M C</searchLink><br /><searchLink fieldCode="AR" term="%22Toth%2C+M%22">Toth, M</searchLink><br /><searchLink fieldCode="AR" term="%22Perales%2C+J+C%22">Perales, J C</searchLink><br /><searchLink fieldCode="AR" term="%22Montefeltro%2C+A%22">Montefeltro, A</searchLink><br /><searchLink fieldCode="AR" term="%22Artigas%2C+F%22">Artigas, F</searchLink> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Molecular+Psychiatry%22">Molecular Psychiatry</searchLink>. Jun2012, Vol. 17 Issue 6, p612-623. 12p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Mental+depression%22">Mental depression</searchLink><br /><searchLink fieldCode="DE" term="%22Serotonin+uptake+inhibitors%22">Serotonin uptake inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Autoreceptors%22">Autoreceptors</searchLink><br /><searchLink fieldCode="DE" term="%22Antidepressants%22">Antidepressants</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+polymorphisms%22">Genetic polymorphisms</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Depression is a major health problem worldwide. Most prescribed anti-depressants, the selective serotonin reuptake inhibitors (SSRI) show limited efficacy and delayed onset of action, partly due to the activation of somatodendritic 5-HT1A-autoreceptors by the excess extracellular serotonin (5-HT) produced by SSRI in the raphe nuclei. Likewise, 5-HT1A receptor (5-HT1AR) gene polymorphisms leading to high 5-HT1A-autoreceptor expression increase depression susceptibility and decrease treatment response. In this study, we report on a new treatment strategy based on the administration of small-interfering RNA (siRNA) to acutely suppress 5-HT1A-autoreceptor-mediated negative feedback mechanisms. We developed a conjugated siRNA (C-1A-siRNA) by covalently binding siRNA targeting 5-HT1A receptor mRNA with the SSRI sertraline in order to concentrate it in serotonin axons, rich in serotonin transporter (SERT) sites. The intracerebroventricular (i.c.v.) infusion of C-1A-siRNA to mice resulted in its selective accumulation in serotonin neurons. This evoked marked anti-depressant-like effects in the forced swim and tail suspension tests, but did not affect anxiety-like behaviors in the elevated plus-maze. In parallel, C-1A-siRNA administration markedly decreased 5-HT1A-autoreceptor expression and suppressed 8-OH-DPAT-induced hypothermia (a pre-synaptic 5-HT1AR effect in mice) without affecting post-synaptic 5-HT1AR expression in hippocampus and prefrontal cortex. Moreover, i.c.v. C-1A-siRNA infusion augmented the increase in extracellular serotonin evoked by fluoxetine in prefrontal cortex to the level seen in 5-HT1AR knockout mice. Interestingly, intranasal C-1A-siRNA administration produced the same effects, thus opening the way to the therapeutic use of C-1A-siRNA. Hence, C-1A-siRNA represents a new approach to treat mood disorders as monotherapy or in combination with SSRI. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
| PLink | https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=75394612 |
| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1038/mp.2011.92 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 12 StartPage: 612 Subjects: – SubjectFull: Mental depression Type: general – SubjectFull: Serotonin uptake inhibitors Type: general – SubjectFull: Autoreceptors Type: general – SubjectFull: Antidepressants Type: general – SubjectFull: Genetic polymorphisms Type: general Titles: – TitleFull: Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Bortolozzi, A – PersonEntity: Name: NameFull: Castañé, A – PersonEntity: Name: NameFull: Semakova, J – PersonEntity: Name: NameFull: Santana, N – PersonEntity: Name: NameFull: Alvarado, G – PersonEntity: Name: NameFull: Cortés, R – PersonEntity: Name: NameFull: Ferrés-Coy, A – PersonEntity: Name: NameFull: Fernández, G – PersonEntity: Name: NameFull: Carmona, M C – PersonEntity: Name: NameFull: Toth, M – PersonEntity: Name: NameFull: Perales, J C – PersonEntity: Name: NameFull: Montefeltro, A – PersonEntity: Name: NameFull: Artigas, F IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 06 Text: Jun2012 Type: published Y: 2012 Identifiers: – Type: issn-print Value: 13594184 Numbering: – Type: volume Value: 17 – Type: issue Value: 6 Titles: – TitleFull: Molecular Psychiatry Type: main |
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