PMID- 26297535
OWN - NLM
STAT- MEDLINE
DCOM- 20160830
LR  - 20211203
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Linking)
VI  - 99
DP  - 2015 Dec
TI  - Activation of mTOR dependent signaling pathway is a necessary mechanism of 
      antidepressant-like activity of zinc.
PG  - 517-26
LID - S0028-3908(15)30071-X [pii]
LID - 10.1016/j.neuropharm.2015.08.026 [doi]
AB  - The rapid antidepressant response to the N-methyl-D-aspartate (NMDA) receptor 
      antagonists is mediated by activation of the mammalian target of the rapamycin 
      (mTOR) signaling pathway, an increase in the synthesis of synaptic proteins and 
      formation of new synapses in the prefrontal cortex (PFC) of rats. Zinc (Zn), 
      which is a potent NMDA receptor antagonist, exerts antidepressant-like effects in 
      screening tests and models of depression. We focused these studies in 
      investigating whether activation of the mTOR signaling pathway is also a 
      necessary mechanism of the antidepressant-like activity of Zn. We observed that a 
      single injection of Zn (5 mg/kg) induced an increase in the phosphorylation of 
      mTOR and p70S6K 30 min and 3 h after Zn treatment at time points when Zn produced 
      also an antidepressant-like effect in the forced swim test (FST). Furthermore, Zn 
      administered 3 h before the decapitation increased the level of brain derived 
      neurotrophic factor (BDNF), GluA1 and synapsin I. An elevated level of GluA1 and 
      synapsin I was still observed 24 h after the Zn treatment, although Zn did not 
      produce any effects in the FST at that time point. We also observed that 
      pretreatment with rapamycin (mTORC1 inhibitor), LY294002 (PI3K inhibitor), H-89 
      (PKA inhibitor) and GF109203X (PKC inhibitor) blocked the antidepressant-like 
      effect of Zn in FST in rats and blocks Zn-induced activation of mTOR signaling 
      proteins (analyzed 30 min after Zn administration). These studies indicated that 
      the antidepressant-like activity of Zn depends on the activation of mTOR 
      signaling and other signaling pathways related to neuroplasticity, which can 
      indirectly modulate mTOR function.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Szewczyk, Bernadeta
AU  - Szewczyk B
AD  - Department of Neurobiology, Institute of Pharmacology, Polish Academy of 
      Sciences, Smetna 12, 31-343 Krakow, Poland. Electronic address: 
      szewczyk@if-pan.krakow.pl.
FAU - Pochwat, Bartlomiej
AU  - Pochwat B
AD  - Department of Neurobiology, Institute of Pharmacology, Polish Academy of 
      Sciences, Smetna 12, 31-343 Krakow, Poland.
FAU - Rafalo, Anna
AU  - Rafalo A
AD  - Department of Neurobiology, Institute of Pharmacology, Polish Academy of 
      Sciences, Smetna 12, 31-343 Krakow, Poland.
FAU - Palucha-Poniewiera, Agnieszka
AU  - Palucha-Poniewiera A
AD  - Department of Neurobiology, Institute of Pharmacology, Polish Academy of 
      Sciences, Smetna 12, 31-343 Krakow, Poland.
FAU - Domin, Helena
AU  - Domin H
AD  - Department of Neurobiology, Institute of Pharmacology, Polish Academy of 
      Sciences, Smetna 12, 31-343 Krakow, Poland.
FAU - Nowak, Gabriel
AU  - Nowak G
AD  - Department of Neurobiology, Institute of Pharmacology, Polish Academy of 
      Sciences, Smetna 12, 31-343 Krakow, Poland; Department of Pharmacobiology, 
      Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150819
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Antidepressive Agents)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (Synapsins)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - J41CSQ7QDS (Zinc)
RN  - TFZ3H25BS1 (glutamate receptor ionotropic, AMPA 1)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/*pharmacology
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors/metabolism
MH  - Depressive Disorder/*drug therapy/metabolism
MH  - Disease Models, Animal
MH  - Enzyme Inhibitors/pharmacology
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Multiprotein Complexes/antagonists & inhibitors/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Prefrontal Cortex/*drug effects/metabolism
MH  - Protein Kinase C/antagonists & inhibitors/metabolism
MH  - Rats, Sprague-Dawley
MH  - Receptors, AMPA/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction/drug effects
MH  - Synapsins/metabolism
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
MH  - Zinc/*pharmacology
OTO - NOTNLM
OT  - FST
OT  - PI3K
OT  - PKA
OT  - PKC
OT  - Zinc
OT  - mTOR
EDAT- 2015/08/25 06:00
MHDA- 2016/08/31 06:00
CRDT- 2015/08/23 06:00
PHST- 2015/03/06 00:00 [received]
PHST- 2015/07/23 00:00 [revised]
PHST- 2015/08/16 00:00 [accepted]
PHST- 2015/08/23 06:00 [entrez]
PHST- 2015/08/25 06:00 [pubmed]
PHST- 2016/08/31 06:00 [medline]
AID - S0028-3908(15)30071-X [pii]
AID - 10.1016/j.neuropharm.2015.08.026 [doi]
PST - ppublish
SO  - Neuropharmacology. 2015 Dec;99:517-26. doi: 10.1016/j.neuropharm.2015.08.026. 
      Epub 2015 Aug 19.