PMID- 27004790
OWN - NLM
STAT- MEDLINE
DCOM- 20170209
LR  - 20211204
IS  - 1432-2072 (Electronic)
IS  - 0033-3158 (Linking)
VI  - 233
IP  - 11
DP  - 2016 Jun
TI  - Rapamycin blocks the antidepressant effect of ketamine in task-dependent manner.
PG  - 2077-2097
LID - 10.1007/s00213-016-4256-3 [doi]
AB  - OBJECTIVE: The aim of our study was to test whether ketamine produces an 
      antidepressant effect in animal model of olfactory bulbectomy and assess the role 
      of mammalian target of rapamycin (mTOR) pathway in ketamine's antidepressant 
      effect. METHODS: Bulbectomized (OBX) rats and sham controls were assigned to four 
      subgroups according to the treatment they received (ketamine, saline, ketamine + 
      rapamycin, and saline + rapamycin). The animals were subjected to open field 
      (OF), elevated plus maze (EPM), passive avoidance (PA), Morris water maze (MWM), 
      and Carousel maze (CM) tests. Blood samples were collected before and after drug 
      administration for analysis of phosphorylated mTOR level. After behavioral 
      testing, brains were removed for evaluation of brain-derived neurotrophic factor 
      (BDNF) in prefrontal cortex (PFC) and hippocampus. RESULTS: Ketamine normalized 
      hyperactivity of OBX animals in EPM and increased the time spent in open arms. 
      Rapamycin pretreatment resulted in elimination of ketamine effect in EPM test. In 
      CM test, ketamine + rapamycin administration led to cognitive impairment not 
      observed in saline-, ketamine-, or saline + rapamycin-treated OBX rats. 
      Prefrontal BDNF content was significantly decreased, and level of mTOR was 
      significantly elevated in OBX groups. CONCLUSIONS: OBX animals significantly 
      differed from sham controls in most of the tests used. Treatment had more 
      profound effect on OBX phenotype than controls. Pretreatment with rapamycin 
      eliminated the anxiolytic and antidepressant effects of ketamine in 
      task-dependent manner. The results indicate that ketamine + rapamycin application 
      resulted in impaired stress responses manifested by cognitive deficits in active 
      place avoidance (CM) test. Intensity of stressor (mild vs. severe) used in the 
      behavioral tests had opposite effect on controls and on OBX animals.
FAU - Holubova, Kristina
AU  - Holubova K
AD  - The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., 
      Videnska 1083, 14220, Prague, Czech Republic.
AD  - National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, 
      Czech Republic.
FAU - Kleteckova, Lenka
AU  - Kleteckova L
AD  - The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., 
      Videnska 1083, 14220, Prague, Czech Republic.
AD  - National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, 
      Czech Republic.
FAU - Skurlova, Martina
AU  - Skurlova M
AD  - The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., 
      Videnska 1083, 14220, Prague, Czech Republic.
AD  - National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, 
      Czech Republic.
FAU - Ricny, Jan
AU  - Ricny J
AD  - National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, 
      Czech Republic.
FAU - Stuchlik, Ales
AU  - Stuchlik A
AD  - The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., 
      Videnska 1083, 14220, Prague, Czech Republic.
FAU - Vales, Karel
AU  - Vales K
AD  - The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., 
      Videnska 1083, 14220, Prague, Czech Republic. vales@biomed.cas.cz.
AD  - National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, 
      Czech Republic. vales@biomed.cas.cz.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160323
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (Antidepressive Agents)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 690G0D6V8H (Ketamine)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/*pharmacology
MH  - Anxiety/psychology
MH  - Avoidance Learning/drug effects
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Hippocampus/drug effects/metabolism
MH  - Ketamine/*antagonists & inhibitors/*pharmacology
MH  - Male
MH  - Maze Learning/drug effects
MH  - Olfactory Bulb/physiology
MH  - Prefrontal Cortex/drug effects/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/drug effects/metabolism
OTO - NOTNLM
OT  - Antidepressants
OT  - Anxiety
OT  - BDNF
OT  - Bulbectomy
OT  - Cognitive deficit
OT  - Ketamine
OT  - Rapamycin
OT  - mTOR
EDAT- 2016/03/24 06:00
MHDA- 2017/02/10 06:00
CRDT- 2016/03/24 06:00
PHST- 2015/10/05 00:00 [received]
PHST- 2016/02/21 00:00 [accepted]
PHST- 2016/03/24 06:00 [entrez]
PHST- 2016/03/24 06:00 [pubmed]
PHST- 2017/02/10 06:00 [medline]
AID - 10.1007/s00213-016-4256-3 [pii]
AID - 10.1007/s00213-016-4256-3 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2016 Jun;233(11):2077-2097. doi: 
      10.1007/s00213-016-4256-3. Epub 2016 Mar 23.