title: Acute systemic rapamycin induces neurobehavioral alterations in rats.
abstract: 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.
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany. Electronic address: martin.hadamitzky@uk-essen.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Hadamitzky
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital Essen, 45122 Essen, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Herring
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital Essen, 45122 Essen, Germany.
authors.forename: Kathy
authors.initials: K
authors.lastname: Keyvani
authors.affiliation: Center of Phenogenomics, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Raphael
authors.initials: R
authors.lastname: Doenlen
authors.affiliation: Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, 04107 Leipzig, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Krügel
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Bösche
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Orlowski
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Engler
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schedlowski
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001007:Anxiety / Q000139:chemically induced*; D004569:Electroencephalography; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D012697:Serine Endopeptidases / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000633:toxicity*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D007166:Immunosuppressive Agents; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; C485430:Klk8 protein, rat; D012697:Serine Endopeptidases; D020123:Sirolimus
keywords: Amygdala; Anxiety; FKBP51; KLK8/Neuropsin; Rapamycin; mTOR