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Phosphodiesterase inhibition and modulation of corticostriatal and hippocampal circuits: Clinical overview and translational considerations

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Abstract

The corticostriatal and hippocampal circuits contribute to the neurobiological underpinnings of several neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease and schizophrenia. Based on biological function, these circuits can be clustered into motor circuits, associative/cognitive circuits and limbic circuits. Together, dysfunctions in these circuits produce the wide range of symptoms observed in related neuropsychiatric disorders. Intracellular signaling in these circuits is largely mediated through the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway with an additional role for the cyclic guanosine monophosphate (cGMP)/ protein kinase G (PKG) pathway, both of which can be regulated by phosphodiesterase inhibitors (PDE inhibitors). Through their effects on cAMP response element-binding protein (CREB) and Dopamine- and cAMP-Regulated PhosphoProtein MR 32 kDa (DARPP-32), cyclic nucleotide pathways are involved in synaptic transmission, neuron excitability, neuroplasticity and neuroprotection. In this clinical review, we provide an overview of the current clinical status, discuss the general mechanism of action of PDE inhibitors in relation to the corticostriatal and hippocampal circuits and consider several translational challenges.

    Research areas

  • Journal Article, Review, PROTEIN-KINASE-A, CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES, Corticostriatal circuits, Clinical review, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, OBSTRUCTIVE PULMONARY-DISEASE, Cyclic nucleotides, MAJOR DEPRESSIVE DISORDER, PLACEBO-CONTROLLED TRIAL, LONG-TERM POTENTIATION, CEREBRAL-BLOOD-FLOW, MEDIUM SPINY NEURONS, Hippocampus, ANTIDEPRESSANT TREATMENT RESPONSE, Phosphodiesterase inhibitors
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Details

Original languageEnglish
Pages (from-to)233-254
Number of pages22
JournalNeuroscience and Biobehavioral Reviews
Volume87
DOIs
Publication statusPublished - Apr 2018