TY - JOUR T1 - Phosphodiesterase 10A Inhibitor Activity in Preclinical Models of the Positive, Cognitive, and Negative Symptoms of Schizophrenia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 574 LP - 590 DO - 10.1124/jpet.109.155994 VL - 331 IS - 2 AU - Steven M. Grauer AU - Virginia L. Pulito AU - Rachel L. Navarra AU - Michele P. Kelly AU - Cody Kelley AU - Radka Graf AU - Barbara Langen AU - Sheree Logue AU - Julie Brennan AU - Lixin Jiang AU - Erik Charych AU - Ute Egerland AU - Feng Liu AU - Karen L. Marquis AU - Michael Malamas AU - Thorsten Hage AU - Thomas A. Comery AU - Nicholas J. Brandon Y1 - 2009/11/01 UR - http://jpet.aspetjournals.org/content/331/2/574.abstract N2 - 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. © 2009 by The American Society for Pharmacology and Experimental Therapeutics ER -