Phosphodiesterase 10A inhibitor, MP-10 (PF-2545920), produces greater induction of c-Fos in dopamine D2 neurons than in D1 neurons in the neostriatum

Wilson, Jonathan M.; Ogden, Ann Marie L.; Loomis, Sally; Gilmour, Gary; Baucum, Anthony J.; Belecky-Adams, Teri L.; Merchant, Kalpana

doi:10.1016/j.neuropharm.2015.08.008

Cited by 32 publications

(20 citation statements)

References 31 publications

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“…In these mice, we pinpointed both D1R expression and activation. 40,41 Bright light selectively activated the D1Rþ cells in HCs and BCs, especially in D1Rþ ON-BCs, and effectively inhibited FDM development, whereas BL-induced inhibition of FDM development and ocular elongation was completely reversed by the D1R antagonist, SCH39166. Thus, activation of the D1R (likely D1R in BCs of the ON pathway) contributes to the inhibitory effect of BL on FDM.…”

Section: Discussionmentioning

confidence: 99%

“…48,49 c-Fos is a general activity marker and a downstream target of D1R activation. 40,41 Thus, c-fos expression levels in these cell types provide readout of D1R activity. Indeed, c-fos expression has been shown to be activated by light in both excitable cells such as NOSþ AC and nonexcitable cholinergic ACs in rabbit cells.…”

Section: Bl Selectively Activates/(recruits) D1r Signaling In the On mentioning

confidence: 99%

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Bright Light Suppresses Form-Deprivation Myopia Development With Activation of Dopamine D1 Receptor Signaling in the ON Pathway in Retina

Chen

Zhi

Ruan

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Chen S, Zhi Z, Ruan Q, et al. Bright light suppresses form-deprivation myopia development with activation of dopamine D1 receptor signaling in the ON pathway in retina. Invest Ophthalmol Vis Sci. 2017;58:230658: -231658: . DOI:10.1167 PURPOSE. To determine whether dopamine receptor D1 (D1R) signaling pathway activation by bright light (BL) in specific retinal neuronal cell types contributes to inhibiting formdeprivation myopia (FDM) in mice.METHODS. Mice (3-weeks old) were raised under either normal light (NL: 100-200 lux) or BL (2500-5000 lux) conditions with or without form deprivation. Refraction changes were evaluated with an eccentric infrared photorefractor, and ocular axial components with optical coherence tomography. The D1R antagonist, SCH39166, was intraperitoneally injected daily to evaluate if BL mediates declines in FDM development through D1R activation. Six different biomarkers of retinal neuronal types delineated differential distribution of D1R expression. cFos and phosphorylated tyrosine hydroxylase (p-TH) immunofluorescent staining evaluated D1R receptor activation and dopamine synthesis, respectively. CONCLUSIONS. Bright light increases D1R activity in the BCs of the ON pathway, which is associated with less myopic shift and ocular elongation than those occurring in NL. These declines suggest that increased D1R activity in the ON pathway contributes to the BL suppression of FDM development in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Bl Selectively Activates/(recruits) D1r Signaling In the On mentioning

confidence: 99%

Bright Light Suppresses Form-Deprivation Myopia Development With Activation of Dopamine D1 Receptor Signaling in the ON Pathway in Retina

Chen

Zhi

Ruan

et al. 2017

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

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“…Taken together, these data indicate that activation of cAMP signaling by blocking PDE10A in striatal projection neurons facilitates corticostriatal transmission and potentiates the excitatory effects of AMPA and NMDA receptor signaling. The behavioral effects of PDE10A inhibitors have been attributed to a greater impact on indirect striatal pathway neurons (Kehler and Nielsen, 2011; Nishi et al, 2008; Nishi et al, 2011; Polito et al, 2015; Threlfell et al, 2009; Wilson et al, 2015). Simpson and colleagues reported that increased D 2 receptor activity in the striatum may alter cognition by disrupting the integration of information from cortical projections (Simpson et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Effects of a novel phosphodiesterase 10A inhibitor in non-human primates: A therapeutic approach for schizophrenia with improved side effect profile

Masilamoni

Uthayathas

Koenig³

et al. 2016

Neuropharmacology

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Schizophrenia symptoms are associated with alterations in basal ganglia-cortical networks that include the cyclic nucleotides (cAMP/cGMP) signaling pathways. Phosphodiesterase 10A (PDE10A) inhibitors have been considered as therapeutic agents for schizophrenia because the regulation of cAMP and cGMP in the striatum by PDE10A plays an important role in the signaling mechanisms of the striatal-cortical network, and thereby in cognitive function. In the present study we assessed in non-human primates (NHPs) the effects of a novel PDE10A inhibitor (FRM-6308) that has demonstrated high potency and selectivity for human recombinant PDE10A in vitro. The behavioral effects of FRM-6308 in a dose range were determined in rhesus monkeys using a standardized motor disability scale for primates, motor tasks, and the “drug effects on the nervous system” (DENS) scale. The neuronal metabolic effects of FRM-6308 were determined with [(18)F]-fluorodeoxyglucose PET imaging. Results showed that FRM-6308 did not have any specific effects on the motor system at s.c. doses up to 0.32 mg/kg in NHPs, which induced a significant increase in the FDG-SUV in striatum (F 16.069, p < 0.05) and cortical (F 15.181, p < 0.05) regions. Higher doses induced sedation and occasional involuntary movements with clear development of tolerance after repeated exposures. These findings suggest that FRM-6308 has the adequate pharmacological profile to advance testing in clinical trials and demonstrate antipsychotic efficacy of PDE10A inhibition for the treatment of schizophrenia patients.

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“…Recent studies have shown that convergent inputs of direct and indirect pathways contribute to learning (Hikida et al, 2010;Yawata et al, 2012). PDE10A is reported to be expressed in both direct-and indirect-pathway MSNs (Duinen et al, 2015;Nikiforuk et al, 2015;Wilson et al, 2015). The cell type-specific translational profile using translating ribosome affinity purification techniques also suggests that PDE10A is expressed in both pathways (Doyle et al, 2008).…”

Section: Tak-063 Improves Cognitive Functions In Rodent Modelsmentioning

confidence: 99%

The Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves Cognitive Functions Associated with Schizophrenia in Rodent Models

Shiraishi

Suzuki

Harada

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Cognitive deficits in various domains, including recognition memory, attention, impulsivity, working memory, and executive function, substantially affect functional outcomes in patients with schizophrenia. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl) phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4 (1H)-one] is a potent and selective phosphodiesterase 10A inhibitor that produces antipsychotic-like effects in rodent models of schizophrenia. We evaluated the effects of TAK-063 on multiple cognitive functions associated with schizophrenia using naïve and drug-perturbed rodents. TAK-063 at 0.1 and 0.3 mg/kg p.o. improved time-dependent memory decay in object recognition in naïve rats. TAK-063 at 0.1 and 0.3 mg/kg p.o. increased accuracy rate, and TAK-063 at 0.3 mg/kg p.o. reduced impulsivity in a five-choice serial reaction time task in naïve rats. N-methyl-D-aspartate receptor antagonists, such as phencyclidine and MK-801 [(5R,10S)-(1)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], were used to induce working memory deficits relevant to schizophrenia in animals. TAK-063 at 0.3 mg/kg p.o. attenuated both phencyclidine-induced working memory deficits in a Y-maze test in mice and MK-801-induced working memory deficits in an eight-arm radial maze task in rats. An attentional set-shifting task using subchronic phencyclidine-treated rats was used to assess the executive function. TAK-063 at 0.3 mg/kg p.o. reversed cognitive deficits in extradimensional shifts. These findings suggest that TAK-063 has a potential to ameliorate deficits in multiple cognitive domains impaired in schizophrenia.

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Phosphodiesterase 10A inhibitor, MP-10 (PF-2545920), produces greater induction of c-Fos in dopamine D2 neurons than in D1 neurons in the neostriatum

Cited by 32 publications

References 31 publications

Bright Light Suppresses Form-Deprivation Myopia Development With Activation of Dopamine D1 Receptor Signaling in the ON Pathway in Retina

Bright Light Suppresses Form-Deprivation Myopia Development With Activation of Dopamine D1 Receptor Signaling in the ON Pathway in Retina

Effects of a novel phosphodiesterase 10A inhibitor in non-human primates: A therapeutic approach for schizophrenia with improved side effect profile

The Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves Cognitive Functions Associated with Schizophrenia in Rodent Models

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