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Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects

BORTOLOZZI, A ; CASTANE, A ; PERALES, J. C ; MONTEFELTRO, A ; ARTIGAS, F ; SEMAKOVA, J ; SANTANA, N ; ALVARADO, G ; CORTES, R ; FERRES-COY, A ; FERNANDEZ, G ; CARMONA, M. C ; TOTH, M

Molecular psychiatry, 2012-06, Vol.17 (6), p.612-623 [Periódico revisado por pares]

Basingstoke: Nature Publishing Group

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Título:
Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects
Autor: BORTOLOZZI, A ; CASTANE, A ; PERALES, J. C ; MONTEFELTRO, A ; ARTIGAS, F ; SEMAKOVA, J ; SANTANA, N ; ALVARADO, G ; CORTES, R ; FERRES-COY, A ; FERNANDEZ, G ; CARMONA, M. C ; TOTH, M
Assuntos: 8-Hydroxy-2-(di-n-propylamino)tetralin ; 8-Hydroxy-2-(di-n-propylamino)tetralin - antagonists & inhibitors ; 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology ; Administration, Intranasal ; Adult and adolescent clinical studies ; Animals ; Antidepressants ; Antidepressive Agents - therapeutic use ; Anxiety ; Autoreceptors - antagonists & inhibitors ; Autoreceptors - biosynthesis ; Biological and medical sciences ; Depression ; Depression - drug therapy ; Disease Models, Animal ; Drug Combinations ; Drug Design ; Emotional disorders ; Fluoxetine ; Fluoxetine - pharmacology ; Gene polymorphism ; Hippocampus - drug effects ; Hippocampus - metabolism ; Hypothermia ; Hypothermia - chemically induced ; Hypothermia - drug therapy ; Infusions, Intraventricular ; Male ; Medical sciences ; Mental depression ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mood disorders ; mRNA ; Neurochemistry ; Neuropharmacology ; Pharmacology. Drug treatments ; Physiology ; Prefrontal cortex ; Prefrontal Cortex - drug effects ; Prefrontal Cortex - metabolism ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. Psychiatry ; Psychopathology. Psychiatry ; Psychopharmacology ; Raphe nuclei ; Receptor, Serotonin, 5-HT1A - biosynthesis ; Receptor, Serotonin, 5-HT1A - chemistry ; Receptor, Serotonin, 5-HT1A - genetics ; RNA, Small Interfering - therapeutic use ; Serotonergic Neurons - drug effects ; Serotonergic Neurons - metabolism ; Serotonin ; Serotonin S1 receptors ; Serotonin transporter ; Serotonin uptake inhibitors ; Sertraline ; Sertraline - administration & dosage ; Sertraline - chemistry ; siRNA
É parte de: Molecular psychiatry, 2012-06, Vol.17 (6), p.612-623
Descrição: 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-HT(1A)-autoreceptors by the excess extracellular serotonin (5-HT) produced by SSRI in the raphe nuclei. Likewise, 5-HT(1A) receptor (5-HT(1A)R) gene polymorphisms leading to high 5-HT(1A)-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-HT(1A)-autoreceptor-mediated negative feedback mechanisms. We developed a conjugated siRNA (C-1A-siRNA) by covalently binding siRNA targeting 5-HT(1A) 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-HT(1A)-autoreceptor expression and suppressed 8-OH-DPAT-induced hypothermia (a pre-synaptic 5-HT(1A)R effect in mice) without affecting post-synaptic 5-HT(1A)R 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-HT(1A)R 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.
Editor: Basingstoke: Nature Publishing Group
Idioma: Inglês

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Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects

BORTOLOZZI, A ; CASTANE, A ; PERALES, J. C ; MONTEFELTRO, A ; ARTIGAS, F ; SEMAKOVA, J ; SANTANA, N ; ALVARADO, G ; CORTES, R ; FERRES-COY, A ; FERNANDEZ, G ; CARMONA, M. C ; TOTH, M

Basingstoke: Nature Publishing Group

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