Abstract
SummaryAltered 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.
Highlights
Mental health conditions afflict one in four adults in their lifetime, with generalized anxiety being the most commonly diagnosed mental health disorder in Western countries (Griebel and Holmes, 2013)
Altered phosphodiesterase (PDE)-cyclic AMP activity is frequently associated with anxiety disorders, but current therapies act by reducing neuronal excitability rather than targeting PDE-cAMP-mediated signaling pathways
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
Summary
Mental health conditions afflict one in four adults in their lifetime, with generalized anxiety being the most commonly diagnosed mental health disorder in Western countries (Griebel and Holmes, 2013). There is an urgent need for therapeutic targets and therapies for anxiety, and for the development of new animal models of behavior to be incorporated into anxiolytic drug research (Baldwin, 2011). Intracellular levels of cAMP and cGMP are tightly regulated by tissue-specific phosphodiesterases (PDEs) that catalyze cyclic nucleotide hydrolysis. Genetic and pharmacological evidence indicates that the PDE4 genes have an important role in controlling cAMP levels in the CNS and behavior (Maurice et al, 2014; Xu et al, 2011). Underscoring the importance of PDE4 inhibitors in disease, the PDE4 inhibitor rolipram has been reported to have potential as a neuroprotectant, as well as enhance cognition and rescue memory deficits in models of Huntington’s disease, Alzheimer’s disease, diabetes, or following brain injury (DeMarch et al, 2008; Burgin et al, 2010; Cheng et al, 2010; Miao et al, 2015; Titus et al, 2013)
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