ArticlePsychopharmacology2012
Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex.
Article in Psychopharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 62 citations in OpenAlex.
- Pooled it
- Pentoxifylline as an adjunctive in treatment of negative symptoms in chronic schizophrenia: A double-blind, randomized, placebo-controlled trial.CNS neuroscience & therapeutics · 2023Trial
- Preliminary evidence for the phosphodiesterase type-4 inhibitor, roflumilast, in ameliorating cognitive flexibility deficits in patients with schizophrenia.Journal of psychopharmacology (Oxford, England) · 2021Trial
- An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients.Psychopharmacology · 2021Trial
- Genome-wide association study of patient-rated and clinician-rated global impression of severity during antipsychotic treatment.Pharmacogenetics and genomics · 2013Trial
- In the Brain of Phosphodiesterases: Potential Therapeutic Targets for Schizophrenia.Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology · 2025Review
- miRNA profiling of hiPSC-derived neurons from monozygotic twins discordant for schizophrenia.Schizophrenia (Heidelberg, Germany) · 2025Article
- The Genetically Informed Neurobiology of Addiction (GINA) model.Nature reviews. Neuroscience · 2023Review
- Forebrain-specific conditional calcineurin deficiency induces dentate gyrus immaturity and hyper-dopaminergic signaling in mice.Molecular brain · 2022Article
- Variants in regulatory elements of PDE4D associate with major mental illness in the Finnish population.Molecular psychiatry · 2021Article
- Dominant-Negative Attenuation of cAMP-Selective Phosphodiesterase PDE4D Action Affects Learning and Behavior.International journal of molecular sciences · 2020Article
- RasGRP1 is a causal factor in the development of l-DOPA-induced dyskinesia in Parkinson's disease.Science advances · 2020Article
- Dopamine and glutamate in schizophrenia: biology, symptoms and treatment.World psychiatry : official journal of the World Psychiatric Association (WPA) · 2020Article
- Adolescent psychosocial stress enhances sensitization to cocaine exposure in genetically vulnerable mice.Neuroscience research · 2020Article
- Phosphodiesterase 1b (PDE1B) Regulates Spatial and Contextual Memory in Hippocampus.Frontiers in molecular neuroscience · 2019Article
- Dopamine Receptor Blockade Attenuates Purinergic P2X4 Receptor-Mediated Prepulse Inhibition Deficits and Underlying Molecular Mechanisms.Frontiers in cellular neuroscience · 2019Article
- Dunce Phosphodiesterase Acts as a Checkpoint for Drosophila Long-Term Memory in a Pair of Serotonergic Neurons.Neuron · 2018Article
- Inhibition of phosphodiesterases as a strategy to achieve neuroprotection in Huntington's disease.CNS neuroscience & therapeutics · 2018Review
- Altered phosphorylation, electrophysiology, and behavior on attenuation of PDE4B action in hippocampus.BMC neuroscience · 2017Article
- The involvement of DARPP-32 in the pathophysiology of schizophrenia.Oncotarget · 2017Review
Corrections and comments
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Authors and funding
10 authors at 7 institutions in 2 countries.
Funding
Abstract
rationaleAlteration of dopamine neurotransmission in the prefrontal cortex, especially hypofunction of dopamine D1 receptors, contributes to psychotic symptoms and cognitive deficit in schizophrenia. D1 receptors signal through the cAMP/PKA second messenger cascade, which is modulated by phosphodiesterase (PDE) enzymes that hydrolyze and inactivate cyclic nucleotides. Though several PDEs are expressed in cortical neurons, the PDE4 enzyme family (PDE4A-D) has been implicated in the control of cognitive function. The best studied isoform, PDE4B, interacts with a schizophrenia susceptibility factor, disrupted in schizophrenia 1 (DISC1).
objectivesWe explore the control of mouse frontal cortex dopamine D1 receptor signaling and associated behavior by PDE4.
resultsInhibition of PDE4 by rolipram induced activation of cAMP/PKA signaling in cortical slices and in vivo, leading to the phosphorylation of DARPP-32 and other postsynaptic and presynaptic PKA-substrates. Rolipram also enhanced DARPP-32 phosphorylation invoked by D1 receptor activation. Immunohistochemical studies demonstrated PDE4A, PDE4B, and PDE4D expression in DARPP-32-positive neurons in layer VI of frontal cortex, most likely in D1 receptor-positive, glutamatergic corticothalamic pyramidal neurons. Furthermore, the ability of rolipram treatment to improve the performance of mice in a sensorimotor gating test was DARPP-32-dependent.
conclusionsPDE4, which is co-expressed with DARPP-32 in D1 receptor-positive cortical pyramidal neurons in layer VI, modulates the level of D1 receptor signaling and DARPP-32 phosphorylation in the frontal cortex, likely influencing cognitive function. These biochemical and behavioral actions of PDE4 inhibitors may contribute to the hypothesized antipsychotic actions of this class of compounds.
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Registered trials
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.