title: MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish.
abstract: Altered phosphodiesterase (PDE)-cyclic AMP (cAMP) activity is frequently associated with anxiety disorders, but current therapies act by reducing neuronal excitability rather than targeting PDE-cAMP-mediated signaling pathways. Here, we report the novel repositioning of anti-cancer MEK inhibitors as anxiolytics in a zebrafish model of anxiety-like behaviors. PDE inhibitors or activators of adenylate cyclase cause behaviors consistent with anxiety in larvae and adult zebrafish. Small-molecule screening identifies MEK inhibitors as potent suppressors of cAMP anxiety behaviors in both larvae and adult zebrafish, while causing no anxiolytic behavioral effects on their own. The mechanism underlying cAMP-induced anxiety is via crosstalk to activation of the RAS-MAPK signaling pathway. We propose that targeting crosstalk signaling pathways can be an effective strategy for mental health disorders, and advance the repositioning of MEK inhibitors as behavior stabilizers in the context of increased cAMP.
authors.affiliation: MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, UK; Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XU, UK; Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Department of Biomedical Sciences, Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Pia R
authors.initials: PR
authors.lastname: Lundegaard
authors.affiliation: MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, UK; Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XU, UK; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Corina
authors.initials: C
authors.lastname: Anastasaki
authors.affiliation: Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Grant
authors.affiliation: Actual Analytics Ltd, 2.05 Wilkie Building, 22-23 Teviot Row, Edinburgh EH8 9AG, UK.
authors.forename: Rowland R
authors.initials: RR
authors.lastname: Sillito
authors.affiliation: MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, UK; Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XU, UK; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Zich
authors.affiliation: MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, UK; Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XU, UK; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, UK; Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XU, UK; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Karthika
authors.initials: K
authors.lastname: Paranthaman
authors.affiliation: Department of Biomedical Sciences, Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Anders Peter
authors.initials: AP
authors.lastname: Larsen
authors.affiliation: Actual Analytics Ltd, 2.05 Wilkie Building, 22-23 Teviot Row, Edinburgh EH8 9AG, UK; School of Informatics, Institute for Adaptive and Neural Computation, Informatics Forum, University of Edinburgh, Edinburgh EH8 9AB, UK.
authors.forename: J Douglas
authors.initials: JD
authors.lastname: Armstrong
authors.affiliation: Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: david.porteous@ed.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, UK; Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XU, UK; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: e.patton@igmm.ed.ac.uk.
authors.forename: E Elizabeth
authors.initials: EE
authors.lastname: Patton
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015027:Zebrafish
chemical_list: D004791:Enzyme Inhibitors; D000242:Cyclic AMP; D020930:MAP Kinase Kinase Kinases