Abstract
Following several recent reports that suggest that dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors may present a novel mechanism to treat positive symptoms of schizophrenia, we sought to extend the preclinical characterization of two such compounds, papaverine [1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline] and MP-10 [2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quinoline], in a variety of in vivo and in vitro assays. Both of these compounds were active in a range of antipsychotic models, antagonizing apomorphine-induced climbing in mice, inhibiting conditioned avoidance responding in both rats and mice, and blocking N-methyl-d-aspartate antagonist-induced deficits in prepulse inhibition of acoustic startle response in rats, while improving baseline sensory gating in mice, all of which strengthen previously reported observations. These compounds also demonstrated activity in several assays intended to probe negative symptoms and cognitive deficits, two disease domains that are underserved by current treatments, with both compounds showing an ability to increase sociality in BALB/cJ mice in the social approach/social avoidance assay, enhance social odor recognition in mice and, in the case of papaverine, improve novel object recognition in rats. Biochemical characterization of these compounds has shown that PDE10A inhibitors modulate both the dopamine D1-direct and D2-indirect striatal pathways and regulate the phosphorylation status of a panel of glutamate receptor subunits in the striatum. It is striking that PDE10A inhibition increased the phosphorylation of the (±)-α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor GluR1 subunit at residue serine 845 at the cell surface. Together, our results suggest that PDE10A inhibitors alleviate both dopaminergic and glutamatergic dysfunction thought to underlie schizophrenia, which may contribute to the broad-spectrum efficacy.
- PDE10A, phosphodiesterase 10A
- MP-10, 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethy]-quinoline
- TP-10, 2-{4-[pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline
- MK-801, dizocilpine maleate
- CREB, cAMP-response element-binding protein
- pCREB, phospho-cAMP-response element-binding protein
- DARPP-32, dopamine and cAMP-regulated phosphoprotein of 32-kDa molecular mass
- pDARPP-32, phosphodopamine and cAMP-regulated phosphoprotein of 32-kDa molecular mass
- PKA, protein kinase A
- cGKII, cGMP-dependent kinase type II
- D1, dopamine receptor subtype 1
- D2, dopamine receptor subtype 2
- GluR1, glutamate receptor subunit 1
- pGluR1, phosphoglutamate receptor subunit 1
- GluR2/3, glutamate receptor subunit 2/glutamate receptor subunit 3
- pGluR2/3, phosphoglutamate receptor subunit 2/phosphoglutamate receptor subunit 3
- NMDA, N-methyl-d-aspartate
- NR2B, NMDA receptor subunit 2B
- pNR2B, phospho-NMDA receptor subunit 2B
- AMPA, (±)-α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid
- MSNs, medium spiny neurons
- EPS, extrapyramidal side effects
- ANOVA, analysis of variance
- CAR, conditioned avoidance responding
- NOR, novel object recognition
- SOR, social odor recognition
- PFC, prefrontal cortex
- PPI, prepulse inhibition
- SASA, social approach/social avoidance
- PCR, polymerase chain reaction
- DMSO, dimethyl sulfoxide
- sulfo-NHS-SS-biotin, sulfosuccinimidyl 2-(biotinamido)-ethyl-1,3′-dithiopropionate.
Footnotes
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This work was funded in its entirety by Wyeth Research and Biotie Therapies GmBH.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.155994
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
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S.M.G. and V.L.P. contributed to this work equally.
- Received May 13, 2009.
- Accepted August 4, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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