Evidence map›Paper›PMID 31689714›Full record

ArticleThe international journal of neuropsychopharmacology2020

Balanced Activation of Striatal Output Pathways by Faster Off-Rate PDE10A Inhibitors Elicits Not Only Antipsychotic-Like Effects But Also Procognitive Effects in Rodents.

Akina Harada, Nidhi Kaushal, Kazunori Suzuki, Atsushi Nakatani, Konstantin Bobkov, John A Vekich, Joseph P Doyle, Haruhide Kimura

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The international journal of neuropsychopharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
0.6field-weighted citation impact, top 32% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 17 citations in OpenAlex.

  1. Trial
  2. Review
  3. Review
  4. Article
  5. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 3 institutions in 2 countries.

Akina HaradaNeuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Nidhi KaushalNeuroscience Drug Discovery Unit Research, Takeda California Inc., San Diego, CA.
Kazunori SuzukiNeuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Atsushi NakataniNeuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Konstantin BobkovEarly Target Discovery, Research, Takeda California Inc., San Diego, CA.
John A VekichEarly Target Discovery, Research, Takeda California Inc., San Diego, CA.
Joseph P DoyleEarly Target Discovery, Research, Takeda California Inc., San Diego, CA.
Haruhide KimuraNeuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Takeda (Japan) · JPTarget (United States) · USTakeda (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundFaster off-rate competitive enzyme inhibitors are generally more sensitive than slower off-rate ones to binding inhibition by enzyme substrates. We previously reported that the cyclic adenosine monophosphate concentration in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) may be higher than that in D2-MSNs. Consequently, compared with slower off-rate phosphodiesterase 10A inhibitors, faster off-rate ones comparably activated D2-MSNs but partially activated D1-MSNs. We further investigated the pharmacological profiles of phosphodiesterase 10A inhibitors with different off-rates.

methodsPhosphodiesterase 10A inhibitors with slower (T-609) and faster (T-773) off-rates were used. D1- and D2-MSN activation was assessed by substance P and enkephalin mRNA induction, respectively, in rodents. Antipsychotic-like effects were evaluated by MK-801- and methamphetamine-induced hyperactivity and prepulse inhibition in rodents. Cognition was assessed by novel object recognition task and radial arm maze in rats. Prefrontal cortex activation was evaluated by c-Fos immunohistochemistry in rats. Gene translations in D1- and D2-MSNs were evaluated by translating ribosome affinity purification and RNA sequencing in mice.

resultsCompared with T-609, T-773 comparably activated D2-MSNs but partially activated D1-MSNs. Haloperidol (a D2 antagonist) and T-773, but not T-609, produced antipsychotic-like effects in all paradigms. T-773, but not T-609 or haloperidol, activated the prefrontal cortex and improved cognition. Overall gene translation patterns in D2-MSNs by all drugs and those in D1-MSNs by T-773 and T-609 were qualitatively similar.

conclusionsDifferential pharmacological profiles among those drugs could be attributable to activation balance of D1- and D2-MSNs. The "balanced activation" of MSNs by faster off-rate phosphodiesterase 10A inhibitors may be favorable to treat schizophrenia.

Indexed as

Phosphoric Diester HydrolasesAnimalsAntipsychotic AgentsBehavior, AnimalCorpus StriatumGABAergic NeuronsMaleMaze LearningMice, Inbred C57BLNootropic AgentsPhosphodiesterase InhibitorsPrefrontal CortexRatsRats, Long-EvansRats, Sprague-DawleyReceptors, Dopamine D1Antipsychotic AgentsNootropic AgentsPde10a protein, mousePDE10A protein, ratPhosphodiesterase InhibitorsPhosphoric Diester HydrolasesReceptors, Dopamine D1Receptors, Dopamine D2cognitionmedium spiny neuronsphosphodiesterase 10Aprefrontal cortextranslating ribosome affinity purification

Identifiers

PMID31689714
PMCPMC7098246
OpenAlexW2982796454

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.