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Rapamycin blocks the antidepressant effect of ketamine in task-dependent manner
Kristina Holubova1,2, Lenka Kleteckova1,2, Martina Skurlova1,2
1The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, 14220, Prague, Czech Republic.
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.
Insights
Ketamine shows antidepressant effects in olfactory bulbectomized rats, but rapamycin blocks these benefits by inhibiting the mTOR pathway. This suggests the mammalian target of rapamycin (mTOR) pathway is crucial for ketamine
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Olfactory bulbectomy (OBX) in rats creates an animal model for depression.
- The mammalian target of rapamycin (mTOR) pathway is implicated in various cellular functions, including neuronal plasticity.
Purpose of the Study:
- To investigate the antidepressant effects of ketamine in an OBX rat model.
- To determine the role of the mTOR pathway in mediating ketamine's antidepressant actions.
Main Methods:
- OBX and sham rats were treated with ketamine, saline, ketamine + rapamycin, or saline + rapamycin.
- Behavioral tests included open field, elevated plus maze, passive avoidance, Morris water maze, and Carousel maze.
- Levels of phosphorylated mTOR and brain-derived neurotrophic factor (BDNF) in the prefrontal cortex and hippocampus were analyzed.
Main Results:
- Ketamine normalized hyperactivity and increased open arm exploration in OBX rats in the elevated plus maze.
- Rapamycin pretreatment abolished ketamine's effects in the elevated plus maze and led to cognitive impairment in the Carousel maze.
- OBX rats showed decreased prefrontal BDNF and elevated mTOR levels, which were modulated by ketamine treatment.
Conclusions:
- Ketamine exhibits anxiolytic and antidepressant effects in the OBX rat model, modulated by the mTOR pathway.
- Rapamycin pretreatment inhibits ketamine's therapeutic effects, highlighting the mTOR pathway's critical role.
- Ketamine's antidepressant action is dependent on the mTOR pathway, suggesting it as a potential therapeutic target.
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