ORIGINAL INVESTIGATION Rapamycin blocks the antidepressant effect of ketamine in task-dependent manner Kristina Holubova 1,2 & Lenka Kleteckova 1,2 & Martina Skurlova 1,2 & Jan Ricny 2 & Ales Stuchlik 1 & Karel Vales 1,2 Received: 5 October 2015 /Accepted: 21 February 2016 # Springer-Verlag Berlin Heidelberg 2016 Abstract 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 con- tent was significantly decreased, and level of mTOR was sig- nificantly elevated in OBX groups. Conclusions OBX animals significantly differed from sham controls in most of the tests used. Treatment had more pro- found effect on OBX phenotype than controls. Pretreatment with rapamycin eliminated the anxiolytic and antidepressant effects of ketamine in task-dependent manner. The results in- dicate that ketamine + rapamycin application resulted in im- paired 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 Ketamine . Rapamycin . Antidepressants . Anxiety . Cognitive deficit . Bulbectomy . mTOR . BDNF Introduction The first report of ketamine’ s antidepressant effect after intra- venous infusion comes from Berman and his colleagues (Berman et al. 2000). The single administration of ketamine has therapeutic effect and improves depressive symptoms last- ing up to 7 days (Zarate et al. 2006, 2012; Diazgranados et al. 2010; Murrough et al. 2013a), possibly up to 4 weeks (Ibrahim et al. 2012). The significant improvement was also reported with repeated infusions in treatment-resistant depressive pa- tients (Murrough et al. 2013b; Shiroma et al. 2014). These findings have triggered the immense interest in research of ketamine’ s antidepressant effect and its mechanism of action. Ketamine is a non-competitive NMDA receptor antagonist (Muir and Lees 1995). However, its antidepressant effect can- not be explained solely by inhibition of NMDA receptors. Ketamine administration sets off signaling cascades resulting in rapid antidepressant effect persisting long after the drug had been eliminated from the body (Hijazi et al. 2003). One of the proposed mechanisms of action responsible for ketamine’ s * Karel Vales vales@biomed.cas.cz 1 The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, 14220 Prague, Czech Republic 2 National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, Czech Republic DOI 10.1007/s00213-016-4256-3 /Published online: 23 March 2016 Psychopharmacology (2016) 233:2077–2097