GSK-3 İnhibisyonu Ketamin’in Antidepresan Etkisini Güçlendiriyor

 

Nature Neuropsychopharmacology dergisinin internet sitesinde Mayıs 2013’te yayınlanan bir makalede; eşik altı dozlarda Ketamin’in Lityum ile birlikte kullanıldığında daha güçlü antidepresan etki gösterdiği belirtildi. Makalenin özetini ve linkini ilginize sunuyoruz. – TürkPsikiyatri |
http://www.nature.com/npp/journal/vaop/naam/pdf/npp2013128a.pdf
lithium

 

GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine

Rong-Jian Liu, Manabu Fuchikami, Jason M Dwyer, Ashley E Lepack,Ronald S Duman and George K Aghajanian

Abstract

A single dose of the short-acting NMDA antagonist ketamine produces rapid and prolonged antidepressant effects in treatment resistant patients with major depressive disorder (MDD), which are thought to occur via restoration of synaptic connectivity. However, acute dissociative side effects and eventual fading of antidepressant effects limit widespread clinical use of ketamine. Recent studies in medial prefrontal cortex (mPFC) show that the synaptogenic and antidepressant-like effects of a single standard dose of ketamine in rodents are dependent upon activation of the mTORC1 signaling pathway together with inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3), which relieves its inhibitory in influence on mTOR. Here, we found that the synaptogenic and antidepressant-like effects of a single otherwise subthreshold dose of ketamine were potentiated when given together with a single dose of lithium chloride (a non-selective GSK-3 inhibitor) or a preferential GSK-3β inhibitor; these effects included rapid activation of the mTORC1 signaling pathway, increased inhibitory phosphorylation of GSK-3β, increased synaptic spine density/diameter, increased excitatory postsynaptic currents (EPSCs) in mPFC layer V pyramidal neurons, and antidepressant responses that persist for up to 1 week in the forced-swim test (FST) model of depression. The results demonstrate that low, subthreshold doses of ketamine combined with lithium or a selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating the pivotal role of the GSK-3 pathway in modulating the synaptogenic and antidepressant responses to ketamine. The possible mitigation by GSK-3 inhibitors of the eventual fading of ketamine’s antidepressant effects remains to be explored.

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