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.

• Keywords
• Antidepressants, Anxiety, BDNF, Bulbectomy, Cognitive deficit, Ketamine, Rapamycin, mTOR,
• MeSH
• Antidepressive Agents pharmacology   MeSH
• Maze Learning drug effects   MeSH
• Olfactory Bulb physiology   MeSH
• Hippocampus drug effects   metabolism   MeSH
• Ketamine antagonists & inhibitors   pharmacology   MeSH
• Rats MeSH
• Brain-Derived Neurotrophic Factor metabolism   MeSH
• Rats, Wistar MeSH
• Prefrontal Cortex drug effects   metabolism   MeSH
• Sirolimus pharmacology   MeSH
• TOR Serine-Threonine Kinases drug effects   metabolism   MeSH
• Avoidance Learning drug effects   MeSH
• Anxiety psychology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antidepressive Agents MeSH
• Ketamine MeSH
• Brain-Derived Neurotrophic Factor MeSH
• mTOR protein, rat MeSH Browser
• Sirolimus MeSH
• TOR Serine-Threonine Kinases MeSH