期刊
CHEMISTRY & BIOLOGY
卷 22, 期 10, 页码 1335-1346出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2015.08.010
关键词
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资金
- Medical Research Council
- Wellcome Trust
- NARSAD Distinguished Investigator Award
- Danish National Research Foundation
- University of Edinburgh
- MRC [MC_U127585840, MC_PC_U127585840] Funding Source: UKRI
- Medical Research Council [MC_U127585840, MC_PC_U127585840] Funding Source: researchfish
Altered phosphodiesterase (PDE)-cyclicAMP(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 mechanismunderlying 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.
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