M Toth

Publications (3)34.18 Total impact

• Article: New antidepressant strategy based on acute siRNA silencing of 5-HT1A autoreceptors.

  A Bortolozzi, A Castañé, J Semakova, N Santana, G Alvarado, R Cortés, A Ferrés-Coy, G Fernández, M C Carmona, M Toth, J C Perales, A Montefeltro, F Artigas
  Molecular psychiatry 06/2012; 17(6):567. · 15.05 Impact Factor
• Article: Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects.

  A Bortolozzi, A Castañé, J Semakova, N Santana, G Alvarado, R Cortés, A Ferrés-Coy, G Fernández, M C Carmona, M Toth, J C Perales, A Montefeltro, F Artigas
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  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-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.
  Molecular psychiatry 08/2011; 17(6):612-23. · 15.05 Impact Factor
• Article: In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain.

  A Bortolozzi, L Díaz-Mataix, M Toth, P Celada, F Artigas
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  ABSTRACT: Aripiprazole is an atypical antipsychotic drug with high in vitro affinity for 5-HT(1A), 5-HT(2A) and dopamine (DA) D2 receptors. However, its in vivo actions in the brain are still poorly characterized. The aim was to study the in vivo actions of aripiprazole in the rat and mouse brain. Brain microdialysis and single-unit extracellular recordings were performed. The systemic administration of aripiprazole reduced 5-HT output in the medial prefrontal cortex (mPFC) and dorsal raphe nucleus of the rat. Aripiprazole also reduced extracellular 5-HT in the mPFC of wild-type (WT) but not of 5-HT(1A) (-/-) knockout (KO) mice. Aripiprazole reversed the elevation in extracellular 5-HT output produced by the local application of the 5-HT(2A/2C) receptor agonist DOI in mPFC. Aripiprazole also increased the DA output in mPFC of WT but not of 5-HT(1A) KO mice, as observed for atypical antipsychotic drugs, in contrast to haloperidol. Contrary to haloperidol, which increases the firing rate of DA neurons in the ventral tegmental area (VTA), aripiprazole induced a very moderate reduction in dopaminergic activity. Haloperidol fully reversed the inhibition in dopaminergic firing rate induced by apomorphine, whereas aripiprazole evoked a partial reversal that was significantly different from that evoked by haloperidol and from the spontaneous reversal of dopaminergic activity in rats treated with apomorphine. These results indicate that aripiprazole modulates the in vivo 5-HT and DA release in mPFC through the activation of 5-HT(1A) receptors. Moreover, aripiprazole behaves as a partial agonist at DA D2 autoreceptors in vivo, an action which clearly distinguishes it from haloperidol.
  Psychopharmacologia 05/2007; 191(3):745-58. · 4.08 Impact Factor