title: Pharmacological Inhibition of the Psychiatric Risk Factor FKBP51 Has Anxiolytic Properties.
abstract: Anxiety-related psychiatric disorders represent one of the largest health burdens worldwide. Single nucleotide polymorphisms of the FK506 binding protein 51 (FKBP51) gene have been repeatedly associated with anxiety-related disorders and stress sensitivity. Given the intimate relationship of stress and anxiety, we hypothesized that amygdala FKBP51 may mediate anxiety-related behaviors. Mimicking the stress effect by specifically overexpressing FKBP51 in the basolateral amygdala (BLA) or central amygdala resulted in increased anxiety-related behavior, respectively. In contrast, application of a highly selective FKBP51 point mutant antagonist, following FKBP51(mut) BLA-overexpression, reduced the anxiogenic phenotype. We subsequently tested a novel FKBP51 antagonist, SAFit2, in wild-type mice via BLA microinjections, which reduced anxiety-related behavior. Remarkably, the same effect was observed following peripheral administration of SAFit2. To our knowledge, this is the first in vivo study using a specific FKBP51 antagonist, thereby unraveling the role of FKBP51 and its potential as a novel drug target for the improved treatment of anxiety-related disorders.
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and jhartmann@psych.mpg.de hausch@psych.mpg.de mschmidt@psych.mpg.de.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hartmann
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Wagner
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Steffen
authors.initials: S
authors.lastname: Gaali
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kirschner
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Christian
authors.initials: C
authors.lastname: Kozany
authors.affiliation: Lead Discovery Center GmbH, 44227 Dortmund, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Rühter
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Nina
authors.initials: N
authors.lastname: Dedic
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Häusl
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Lianne
authors.initials: L
authors.lastname: Hoeijmakers
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Sören
authors.initials: S
authors.lastname: Westerholz
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Christian
authors.initials: C
authors.lastname: Namendorf
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Tamara
authors.initials: T
authors.lastname: Gerlach
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Alon
authors.initials: A
authors.lastname: Chen
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Deussing
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and jhartmann@psych.mpg.de hausch@psych.mpg.de mschmidt@psych.mpg.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany, and jhartmann@psych.mpg.de hausch@psych.mpg.de mschmidt@psych.mpg.de.
authors.forename: Mathias V
authors.identifier: http://orcid.org/0000-0002-3788-2268
authors.initials: MV
authors.lastname: Schmidt
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections / Q000379:methods; D012307:Risk Factors; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D014151:Anti-Anxiety Agents; D008024:Ligands; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: FKBP51; PTSD; amygdala; antidepressants; anxiety