Behavioral characterization of mice deficient in the phosphodiesterase-10A (PDE10A) enzyme on a C57/Bl6N congenic background

Siuciak, Judith A.; McCarthy, Sheryl A.; Chapin, Douglas S.; Martin, A.; Harms, John F.; Schmidt, Christopher J.

doi:10.1016/j.neuropharm.2007.10.009

Cited by 62 publications

(44 citation statements)

References 34 publications

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“…Behavioral phenotypes of PDE10A knockout mice are similar to the behavioral effects of PDE10A inhibitors (22,31,32) (Table 1). PDE10A knockout mice with genetic background of DBA1LacJ (PDE10A DBA ) and C57BL/6N (PDE10A C57 ) show a decrease in spontaneous locomotor activity and PCP/MK-801-stimulated locomotor activity and a delayed acquisition or decrease in conditioned avoidance responding.…”

Section: Behavioral Phenotypes Of Pde10a Knockout Micementioning

confidence: 74%

Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Biochemical and Behavioral Profiles of Phosphodiesterase Inhibition in Dopaminergic Neurotransmission

Nishi

Snyder

2010

J Pharmacol Sci

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Abstract. Dopamine plays a central role in the regulation of psychomotor functions. The effect of dopamine is largely mediated through the cAMP/PKA signaling cascade and therefore controlled by phosphodiesterases (PDEs). Multiple PDEs with different substrate specificities and subcellular localization are expressed in the striatum, and the functional roles of PDE10A, PDE4, and PDE1B are extensively studied. Biochemical and behavioral profiles of PDE inhibition by selective inhibitors and/or genetic deletion related to dopaminergic neurotransmission are compared among those PDEs. The inhibition of PDE up-regulates cAMP/PKA signaling in three neuronal subtypes, resulting in the stimulation of dopamine synthesis at dopaminergic terminals, the inhibition of dopamine D 2 -receptor signaling in striatopallidal neurons, and the stimulation of dopamine D 1 -receptor signaling in striatonigral neurons. Predominant roles of PDE families or isoforms are implicated in each neuronal subtype: PDE4 at dopaminergic terminals, PDE10A and PDE4 in striatopallidal neurons, and PDE1B in striatonigral neurons. PDE10A and PDE4 inhibition may exhibit D 2 antagonist-like, antipsychotic effects, whereas PDE1B inhibition may exhibit D 1 agonist-like effects in the striatum. Development of PDE isoform-specific inhibitors is essential for better understanding of the function of each PDE isoform and treatment of neuropsychiatric disorders.

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Section: Behavioral Phenotypes Of Pde10a Knockout Micementioning

confidence: 74%

Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Biochemical and Behavioral Profiles of Phosphodiesterase Inhibition in Dopaminergic Neurotransmission

Nishi

Snyder

2010

J Pharmacol Sci

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“…Since multiple lines of evidence point to the striatum-enriched PDE10A as a potential therapeutic target for schizophrenia and related disorders (Siuciak et al, 2006a,b;Nishi et al, 2008;Schmidt et al, 2008;Siuciak et al, 2008;Grauer et al, 2009;Threlfell et al, 2009), we sought to further characterize the mechanism by which PDE10A localization is regulated. Previous reports suggest that PDE10A protein, but not mRNA, is specifically transported from the cell bodies to the axons and dendrites of medium spiny neurons (Seeger et al, 2003;Coskran et al, 2006;Xie et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…This distribution pattern predicts that PDE10A inhibition might affect basal ganglia circuitry in a manner that is consistent with the potential for antipsychotic efficacy. Indeed, multiple studies using selective PDE10A inhibitors and PDE10A knock-out mutant mice suggest that PDE10A inhibition produces neurochemical, neurophysiological, and behavioral effects predictive of antipsychotic efficacy (Siuciak et al, 2006a,b;Nishi et al, 2008;Schmidt et al, 2008;Siuciak et al, 2008;Grauer et al, 2009;Threlfell et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Interplay of Palmitoylation and Phosphorylation in the Trafficking and Localization of Phosphodiesterase 10A: Implications for the Treatment of Schizophrenia

Charych

Jiang²,

Lo³

et al. 2010

Journal of Neuroscience

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Phosphodiesterase 10A (PDE10A) is a striatum-enriched, dual-specific cyclic nucleotide phosphodiesterase that has gained considerable attention as a potential therapeutic target for psychiatric disorders such as schizophrenia. As such, a PDE10A-selective inhibitor compound, MP-10, has recently entered clinical testing. Since little is known about the cellular regulation of PDE10A, we sought to elucidate the mechanisms that govern its subcellular localization in striatal medium spiny neurons. Previous reports suggest that PDE10A is primarily membrane bound and is transported throughout medium spiny neuron axons and dendrites. Moreover, it has been shown in PC12 cells that the localization of the major splice form, PDE10A2, may be regulated by protein kinase A phosphorylation at threonine 16 (Thr-16). Using an antibody that specifically recognizes phosphorylated Thr-16 (pThr-16) of PDE10A2, we provide evidence that phosphorylation at Thr-16 is critical for the regulation of PDE10A subcellular localization in vivo. Furthermore, we demonstrate in primary mouse striatal neuron cultures that PDE10A membrane association and transport throughout dendritic processes requires palmitoylation of cysteine 11 (Cys-11) of PDE10A2, likely by the palmitoyl acyltransferases DHHC-7 and -19. Finally, we show that Thr-16 phosphorylation regulates PDE10A trafficking and localization by preventing palmitoylation of Cys-11 rather than by interfering with palmitate-lipid interactions. These data support a model whereby PDE10A trafficking and localization can be regulated in response to local fluctuations in cAMP levels. Given this, we propose that excessive striatal dopamine release, as occurs in schizophrenia, might exert differential effects on the regulation of PDE10A localization in the two striatal output pathways.

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“…PDE10A is expressed in both direct (D1) and indirect (D2) pathway neurons, but not in striatal interneurons (Xie et al, 2006). The unique expression patterns of PDE10A in the STR suggest that interference of PDE10A enzyme activity may result in alterations of behaviors regulated by the neuronal circuits (Siuciak et al, 2006(Siuciak et al, , 2008. Inhibition of PDE10A in the direct pathway neurons may lead to the potentiation of D1 receptor signaling, while inhibition of PDE10A in the indirect pathway neurons causes the potentiation of the A2A receptor and inhibition of D2 receptor signaling (Nishi et al, 2008(Nishi et al, , 2011.…”

Section: Abbreviationsmentioning

confidence: 99%

“…Therefore, inhibition of PDE10A has been hypothesized to be beneficial in psychiatric and neurologic diseases involving the basal ganglia, such as schizophrenia (Menniti et al, 2007;Schmidt et al, 2008) and Huntington's disease (Kleiman et al, 2011). Selective inhibitors of PDE10A have been reported to be efficacious in preclinical rodent behavioral models of schizophrenia, such as phencyclidine-stimulated hyperlocomotor activity, prepulse inhibition model, and conditioned avoidance response (Siuciak et al, 2006(Siuciak et al, , 2008Grauer et al, 2009). Moreover, the PDE10A inhibitor 2,pyrazol-3-yl]phenoxy]methyl]quinoline) has been demonstrated to ameliorate pathology and locomotor behavior in rat and R6/2 mouse models of Huntington's disease (Giampà et al, 2009(Giampà et al, , 2010.…”

Section: Abbreviationsmentioning

confidence: 99%

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

Chen

Lester-Zeiner

Shi

et al. 2014

J Pharmacol Exp Ther

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Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d] imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [ 3 H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [18 F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

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Behavioral characterization of mice deficient in the phosphodiesterase-10A (PDE10A) enzyme on a C57/Bl6N congenic background

Cited by 62 publications

References 34 publications

Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Biochemical and Behavioral Profiles of Phosphodiesterase Inhibition in Dopaminergic Neurotransmission

Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Biochemical and Behavioral Profiles of Phosphodiesterase Inhibition in Dopaminergic Neurotransmission

Interplay of Palmitoylation and Phosphorylation in the Trafficking and Localization of Phosphodiesterase 10A: Implications for the Treatment of Schizophrenia

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

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