Addition of 1 1?M PD0325901 significantly rescued the thigmotaxic effects of PDE4 blockade/cAMP activation within 30C40?min. an effective strategy for mental health Trichostatin-A (TSA) disorders, and advance the repositioning of MEK inhibitors as behavior stabilizers in the context of increased cAMP. Graphical Abstract Open in a separate window Introduction 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 stress, and for the development of new animal models of behavior to be incorporated into anxiolytic drug research (Baldwin, 2011). The second messengers cyclic AMP (cAMP) and cyclic guanosine monophosphate (cGMP) are critical in the signaling that controls learning, memory, and mood (Maurice et?al., 2014, Xu et?al., 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 this genes have an important role in controlling cAMP levels in the CNS and behavior (Maurice et?al., 2014, Xu et?al., 2011). In mammals, PDE4 enzymes comprise four subfamilies (PDE4ACD). Polymorphisms in human Trichostatin-A (TSA) are associated with schizophrenia; we have previously reported complete disruption of the gene in two impartial subjects with psychosis, and that PDE4B and PDE4D interact dynamically with the schizophrenia candidate gene DISC1 to regulate cAMP (Clapcote et?al., 2007, Millar et?al., 2005, Millar et?al., 2007). New PDE4 inhibitors are the focus of intensive drug discovery, not least because recent genome-wide studies indicate that PDE4 may be involved in the pathogenesis of stroke (Nilsson-Ardnor et?al., 2005, Staton et?al., 2006), bone density (Reneland et?al., 2005), and asthma (Hansen et?al., 2000, Himes et?al., 2009). 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 Huntingtons disease, Alzheimers disease, diabetes, or following brain injury (DeMarch et?al., 2008, Burgin et?al., 2010, Cheng Trichostatin-A (TSA) et?al., 2010, Miao et?al., 2015, Titus et?al., 2013). Rolipram is usually highly specific to PDE4 and is effective in mammals; however, it causes severe emesis in human patients, making it unsuitable as a clinical drug (O’Donnell and Zhang, 2004). In?animal studies, pharmacological inhibition of PDE4 can have?anti-depressive, sedative, anxiolytic, anti-psychotic, and cognitive enhancing effects, and can increase neurogenesis, but conversely the drug can have anxiogenic effects in some contexts (Burgin et?al., 2010, Heaslip and Evans, 1995, Li et?al., 2009, Rutten et?al., 2008, Silvestre et?al., 1999, Siuciak et?al., 2007, Zhang et?al., 2002). This range of rolipram-induced behaviors likely reflects the importance of specific PDE4 subtypes in regulating distinct behaviors: genetic studies in mice have revealed that stress is largely regulated by PDE4A KIAA1823 and PDE4B, psychosis by PDE4B, and depressive disorder and cognition by PDE4D (Hansen et?al., 2014, Li et?al., 2011, Siuciak et?al., 2007, Siuciak et?al., 2008, Zhang et?al., 2002, Zhang et?al., 2008). DISC1 and PDE4B may?also be important in the development of depression caused by chronic stress (Zhang et?al., 2015). Notably, the anti-psychotic effects of rolipram and the dependence of these effects on PDE4B are consistent with the association of PDE4B gene disruptions with schizophrenia (Millar et?al., 2005, Trichostatin-A (TSA) Siuciak et?al., 2007, Zhang et?al., 2008). While strong genetic evidence in mice indicates the importance of PDE4A/B in stress (Hansen et?al., 2014, Zhang et?al., 2008), the mechanism through which PDE4-cAMP leads to anxiety remains unknown while being critical for the development of?new therapeutic approaches and targets. In zebrafish, PDE4 inhibitors promote anxiety-like behaviors, including decreased habituation to the startle response, increased activity, and thigmotaxis (wall-hugging) in larvae and adult fish (Best et?al., 2008, Maximino et?al., 2011, Richendrfer et?al., 2012, Schnorr et?al., 2012, Stewart et?al., 2011). Here, we develop a zebrafish model for PDE4-cAMP-mediated anxiety-like behaviors,.
Addition of 1 1?M PD0325901 significantly rescued the thigmotaxic effects of PDE4 blockade/cAMP activation within 30C40?min
