Phosphodiesterase 10A inhibitor MP-10 effects in primates: Comparison with risperidone and mechanistic implications

• Type of Material: Article
• Authors: Subramaniam Uthayathas, Emory University; Gunasingh J. Masilamoni, Emory University; Christopher L. Shaffer, Pfizer Inc.; Christopher J. Schmidt, Pfizer Inc.; Frank S. Menniti, Mnemosyne Pharmaceut Inc.; Stella Papa, Emory University
• Language: English
• Date: 2014-02-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Elsevier Ltd. All rights reserved. CC BY NC ND 4.0.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuropharm.2013.10.015
• Title of Journal or Parent Work: Neuropharmacology
• ISSN: 0028-3908
• Volume: 77
• Start Page: 257
• End Page: 267
• Grant/Funding Information: Dr. Papa is supported by NIH grants NS045962 and NS073994, and this work was also supported by NCRR RR000165 and ORIP/OD OD011132 (Yerkes National Primate Research Center).
• Keywords: LEVODOPA; ANTIPSYCHOTICS; Striatum; Life Sciences & Biomedicine; Neurosciences & Neurology; Schizophrenia; RHESUS-MONKEYS; PDE10A INHIBITION; PDE10A inhibitors; Medium spiny neuron; D-2 receptors; IMMUNOHISTOCHEMICAL LOCALIZATION; BASAL GANGLIA; Pharmacology & Pharmacy; Neurosciences; Phosphodiesterase; STRIATAL NEURONS; MICE DEFICIENT; Science & Technology; FUNCTIONAL-ANATOMY; DOPAMINE-D-2 RECEPTORS
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

Phosphodiesterase 10A (PDE10A) is highly expressed in striatal medium spiny neurons of both the direct and indirect output pathways. Similar to dopamine D2 receptor antagonists acting on indirect pathway neurons, PDE10A inhibitors have shown behavioral effects in rodent models that predict antipsychotic efficacy. These findings have supported the clinical investigation of PDE10A inhibitors as a new treatment for schizophrenia. However, PDE10A inhibitors and D2 antagonists differ in effects on direct pathway and other neurons of the basal ganglia, indicating that these two drug classes may have divergent antipsychotic efficacy and side effect profile. In the present study, we compare the behavioral effects of the selective PDE10A inhibitor MP-10 to those of the clinical standard D2 antagonist risperidone in rhesus monkeys using a standardized motor disability scale for parkinsonian primates and a newly designed "Drug Effects on Nervous System" scale to assess non-motor effects. Behavioral effects of MP-10 correlated with its plasma levels and its regulation of metabolic activity in striatal and cortical regions as measured by FDG-PET imaging. While MP-10 and risperidone broadly impacted similar behavioral domains in the primate, their effects had a different underlying basis. MP-10-treated animals retained the ability to respond but did not engage tasks, whereas risperidone-treated animals retained the motivation to respond but were unable to perform the intended actions. These findings are discussed in light of what is currently known about the modulation of striatal circuitry by these two classes of compounds, and provide insight into interpreting emerging clinical data with PDE10A inhibitors for the treatment of psychotic symptoms.