MEK inhibitors reverse cAMP-mediated anxiety in zebrafish

Pia R. Lundegaard, Corina Anastasaki, Nicola J. Grant, Rowland R. Sillito, Judith Zich, Zhiqiang Zeng, Karthika Paranthaman, Anders Peter Larsen, J. Douglas Armstrong, David J. Porteous, E. Elizabeth Patton

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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 ofMEKinhibitors as behavior stabilizers in the context of increased cAMP.

Original languageEnglish
Pages (from-to)1335-1346
Number of pages12
JournalChemistry and Biology
Volume22
Issue number10
DOIs
StatePublished - Oct 22 2015
Externally publishedYes

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    Lundegaard, P. R., Anastasaki, C., Grant, N. J., Sillito, R. R., Zich, J., Zeng, Z., Paranthaman, K., Larsen, A. P., Armstrong, J. D., Porteous, D. J., & Patton, E. E. (2015). MEK inhibitors reverse cAMP-mediated anxiety in zebrafish. Chemistry and Biology, 22(10), 1335-1346. https://doi.org/10.1016/j.chembiol.2015.08.010