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

Copyright © 2021 Menniti, Chappie and Schmidt..

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:14

Enthalten in:

Frontiers in neuroscience - 14(2020) vom: 25., Seite 600178

Sprache:

Englisch

Beteiligte Personen:

Menniti, Frank S [VerfasserIn]
Chappie, Thomas A [VerfasserIn]
Schmidt, Christopher J [VerfasserIn]

Links:

Volltext

Themen:

Antipsychotic action
Basal ganglia
Cyclic nucleotide phosphodiesterase
Dopamine
Journal Article
Medium spiny neuron
PDE10A
Review
Schizophrenia

Anmerkungen:

Date Revised 10.02.2021

published: Electronic-eCollection

Citation Status PubMed-not-MEDLINE

doi:

10.3389/fnins.2020.600178

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM32112247X