PUBLICATION
MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish
- Authors
- 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.
- ID
- ZDB-PUB-150923-3
- Date
- 2015
- Source
- Chemistry & Biology 22(10): 1335-46 (Journal)
- Registered Authors
- Lundegaard, Pia Rengtved, Patton, E. Elizabeth, Zeng, Zhiqiang
- Keywords
- none
- MeSH Terms
-
- Animals
- Anxiety/drug therapy*
- Behavior, Animal/drug effects
- Cyclic AMP/metabolism*
- Disease Models, Animal
- Enzyme Inhibitors/pharmacology
- Enzyme Inhibitors/therapeutic use*
- Humans
- MAP Kinase Kinase Kinases/antagonists & inhibitors*
- MAP Kinase Kinase Kinases/metabolism
- Zebrafish
- PubMed
- 26388333 Full text @ Chem. Biol.
Citation
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 & Biology. 22(10):1335-46.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping