PMID- 25043732 OWN - NLM STAT- MEDLINE DCOM- 20150511 LR - 20211203 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 273 DP - 2014 Oct 15 TI - Acute systemic rapamycin induces neurobehavioral alterations in rats. PG - 16-22 LID - S0166-4328(14)00439-2 [pii] LID - 10.1016/j.bbr.2014.06.056 [doi] AB - Rapamycin is a drug with antiproliferative and immunosuppressive properties, widely used for prevention of acute graft rejection and cancer therapy. It specifically inhibits the activity of the mammalian target of rapamycin (mTOR), a protein kinase known to play an important role in cell growth, proliferation and antibody production. Clinical observations show that patients undergoing therapy with immunosuppressive drugs frequently suffer from affective disorders such as anxiety or depression. However, whether these symptoms are attributed to the action of the distinct compounds remains rather elusive. The present study investigated in rats neurobehavioral consequences of acute rapamycin treatment. Systemic administration of a single low dose rapamycin (3mg/kg) led to enhanced neuronal activity in the amygdala analyzed by intracerebral electroencephalography and FOS protein expression 90min after drug injection. Moreover, behavioral investigations revealed a rapamycin-induced increase in anxiety-related behaviors in the elevated plus-maze and in the open-field. The behavioral alterations correlated to enhanced amygdaloid expression of KLK8 and FKBP51, proteins that have been implicated in the development of anxiety and depression. Together, these results demonstrate that acute blockade of mTOR signaling by acute rapamycin administration not only causes changes in neuronal activity, but also leads to elevated protein expression in protein kinase pathways others than mTOR, contributing to the development of anxiety-like behavior. Given the pivotal role of the amygdala in mood regulation, associative learning, and modulation of cognitive functions, our findings raise the question whether therapy with rapamycin may induce alterations in patients neuropsychological functioning. CI - Copyright (c) 2014 Elsevier B.V. All rights reserved. FAU - Hadamitzky, Martin AU - Hadamitzky M AD - Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany. Electronic address: martin.hadamitzky@uk-essen.de. FAU - Herring, Arne AU - Herring A AD - Institute of Pathology and Neuropathology, University Hospital Essen, 45122 Essen, Germany. FAU - Keyvani, Kathy AU - Keyvani K AD - Institute of Pathology and Neuropathology, University Hospital Essen, 45122 Essen, Germany. FAU - Doenlen, Raphael AU - Doenlen R AD - Center of Phenogenomics, School of Life Sciences, Ecole Polytechnique Federale de Lausanne, 1015 Lausanne, Switzerland. FAU - Krugel, Ute AU - Krugel U AD - Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, 04107 Leipzig, Germany. FAU - Bosche, Katharina AU - Bosche K AD - Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany. FAU - Orlowski, Kathrin AU - Orlowski K AD - Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany. FAU - Engler, Harald AU - Engler H AD - Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany. FAU - Schedlowski, Manfred AU - Schedlowski M AD - Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany. LA - eng PT - Journal Article DEP - 20140717 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Immunosuppressive Agents) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.21.- (Klk8 protein, rat) RN - EC 3.4.21.- (Serine Endopeptidases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Amygdala/*drug effects/metabolism/physiopathology MH - Animals MH - Anxiety/*chemically induced MH - Electroencephalography MH - Immunosuppressive Agents/administration & dosage/*toxicity MH - Male MH - Motor Activity/drug effects MH - Rats MH - Serine Endopeptidases/metabolism MH - Sirolimus/administration & dosage/*toxicity MH - TOR Serine-Threonine Kinases/antagonists & inhibitors OTO - NOTNLM OT - Amygdala OT - Anxiety OT - FKBP51 OT - KLK8/Neuropsin OT - Rapamycin OT - mTOR EDAT- 2014/07/22 06:00 MHDA- 2015/05/12 06:00 CRDT- 2014/07/22 06:00 PHST- 2014/05/08 00:00 [received] PHST- 2014/06/25 00:00 [revised] PHST- 2014/06/26 00:00 [accepted] PHST- 2014/07/22 06:00 [entrez] PHST- 2014/07/22 06:00 [pubmed] PHST- 2015/05/12 06:00 [medline] AID - S0166-4328(14)00439-2 [pii] AID - 10.1016/j.bbr.2014.06.056 [doi] PST - ppublish SO - Behav Brain Res. 2014 Oct 15;273:16-22. doi: 10.1016/j.bbr.2014.06.056. Epub 2014 Jul 17.