Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications

Pim R A Heckman, Marlies A van Duinen, Eva P P Bollen, Akinori Nishi, Lawrence P Wennogle, Arjan Blokland, Jos Prickaerts

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Abstract

BACKGROUND: The fronto-striatal circuits are the common neurobiological basis for neuropsychiatric disorders, including schizophrenia, Parkinson's disease, Huntington's disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and Tourette's syndrome. Fronto-striatal circuits consist of motor circuits, associative circuits, and limbic circuits. All circuits share 2 common features. First, all fronto-striatal circuits consist of hyper direct, direct, and indirect pathways. Second, all fronto-striatal circuits are modulated by dopamine. Intracellularly, the effect of dopamine is largely mediated through the cyclic adenosine monophosphate/protein kinase A signaling cascade with an additional role for the cyclic guanosine monophosphate/protein kinase G pathway, both of which can be regulated by phosphodiesterases. Phosphodiesterases are thus a potential target for pharmacological intervention in neuropsychiatric disorders related to dopaminergic regulation of fronto-striatal circuits.

METHODS: Clinical studies of the effects of different phosphodiesterase inhibitors on cognition, affect, and motor function in relation to the fronto-striatal circuits are reviewed.

RESULTS: Several selective phosphodiesterase inhibitors have positive effects on cognition, affect, and motor function in relation to the fronto-striatal circuits.

CONCLUSION: Increased understanding of the subcellular localization and unraveling of the signalosome concept of phosphodiesterases including its function and dysfunction in the fronto-striatal circuits will contribute to the design of new specific inhibitors and enhance the potential of phosphodiesterase inhibitors as therapeutics in fronto-striatal circuits.

Original languageEnglish
Article numberpyw030
Number of pages16
JournalInternational Journal of Neuropsychopharmacology
Volume19
Issue number10
Early online date30 Apr 2016
DOIs
Publication statusPublished - Oct 2016

Keywords

  • fronto-striatal circuits
  • dopamine
  • phosphodiesterase
  • phosphodiesterase inhibitors
  • cyclic adenosine monophosphate
  • LONG-TERM POTENTIATION
  • PROTEIN-KINASE-A
  • CYCLIC-AMP PHOSPHODIESTERASES
  • SUBSTANTIA-NIGRA NEURONS
  • QUINOLINIC ACID MODEL
  • R6/2 MOUSE MODEL
  • NEUROTROPHIC FACTOR
  • GENE-EXPRESSION
  • MESSENGER-RNA
  • PDE10A INHIBITORS

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