title: Rapamycin blocks the antidepressant effect of ketamine in task-dependent manner.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, 14220, Prague, Czech Republic.|National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, Czech Republic.
authors.forename: Kristina
authors.initials: K
authors.lastname: Holubova
authors.affiliation: The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, 14220, Prague, Czech Republic.|National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Kleteckova
authors.affiliation: The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, 14220, Prague, Czech Republic.|National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Skurlova
authors.affiliation: National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Ricny
authors.affiliation: The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, 14220, Prague, Czech Republic.
authors.forename: Ales
authors.initials: A
authors.lastname: Stuchlik
authors.affiliation: The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, 14220, Prague, Czech Republic. vales@biomed.cas.cz.|National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, Czech Republic. vales@biomed.cas.cz.
authors.forename: Karel
authors.initials: K
authors.lastname: Vales
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001007:Anxiety / Q000523:psychology; D001362:Avoidance Learning / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009830:Olfactory Bulb / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D007649:Ketamine; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Antidepressants; Anxiety; BDNF; Bulbectomy; Cognitive deficit; Ketamine; Rapamycin; mTOR