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PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?

PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among a...

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Autores principales: Menniti, Frank S., Chappie, Thomas A., Schmidt, Christopher J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855852/
https://www.ncbi.nlm.nih.gov/pubmed/33551724
http://dx.doi.org/10.3389/fnins.2020.600178
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author Menniti, Frank S.
Chappie, Thomas A.
Schmidt, Christopher J.
author_facet Menniti, Frank S.
Chappie, Thomas A.
Schmidt, Christopher J.
author_sort Menniti, Frank S.
collection PubMed
description PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium spiny neurons are components of either the direct or indirect striatal output pathways. Selective activation of indirect pathway medium spiny neurons by dopamine D2 receptor antagonists is putatively a key element in the mechanism of their antipsychotic efficacy. While PDE10A is expressed in all medium spiny neurons, studies in rodents indicated that PDE10A inhibition has behavioral effects in several key assays that phenocopy dopamine D2 receptor inhibition. This finding gave rise to the hypothesis that PDE10A inhibition also preferentially activates indirect pathway medium spiny neurons, a hypothesis that is consistent with electrophysiological, neurochemical, and molecular effects of PDE10A inhibitors. These data underwrote industry-wide efforts to investigate and develop PDE10A inhibitors as novel antipsychotics. Disappointingly, PDE10A inhibitors from 3 companies failed to evidence antipsychotic activity in patients with schizophrenia to the same extent as standard-of-care D2 antagonists. Given the notable similarities between PDE10A inhibitors and D2 antagonists, gaining an understanding of why only the latter class is antipsychotic affords a unique window into the basis for this therapeutic efficacy. With this in mind, we review the data on PDE10A inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia.
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spelling pubmed-78558522021-02-04 PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action? Menniti, Frank S. Chappie, Thomas A. Schmidt, Christopher J. Front Neurosci Neuroscience PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium spiny neurons are components of either the direct or indirect striatal output pathways. Selective activation of indirect pathway medium spiny neurons by dopamine D2 receptor antagonists is putatively a key element in the mechanism of their antipsychotic efficacy. While PDE10A is expressed in all medium spiny neurons, studies in rodents indicated that PDE10A inhibition has behavioral effects in several key assays that phenocopy dopamine D2 receptor inhibition. This finding gave rise to the hypothesis that PDE10A inhibition also preferentially activates indirect pathway medium spiny neurons, a hypothesis that is consistent with electrophysiological, neurochemical, and molecular effects of PDE10A inhibitors. These data underwrote industry-wide efforts to investigate and develop PDE10A inhibitors as novel antipsychotics. Disappointingly, PDE10A inhibitors from 3 companies failed to evidence antipsychotic activity in patients with schizophrenia to the same extent as standard-of-care D2 antagonists. Given the notable similarities between PDE10A inhibitors and D2 antagonists, gaining an understanding of why only the latter class is antipsychotic affords a unique window into the basis for this therapeutic efficacy. With this in mind, we review the data on PDE10A inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia. Frontiers Media S.A. 2021-01-20 /pmc/articles/PMC7855852/ /pubmed/33551724 http://dx.doi.org/10.3389/fnins.2020.600178 Text en Copyright © 2021 Menniti, Chappie and Schmidt. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Menniti, Frank S.
Chappie, Thomas A.
Schmidt, Christopher J.
PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?
title PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?
title_full PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?
title_fullStr PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?
title_full_unstemmed PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?
title_short PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?
title_sort pde10a inhibitors—clinical failure or window into antipsychotic drug action?
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855852/
https://www.ncbi.nlm.nih.gov/pubmed/33551724
http://dx.doi.org/10.3389/fnins.2020.600178
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