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

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...

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Bibliographic Details
Published in:	The international journal of neuropsychopharmacology Vol. 19; no. 10; p. pyw030
Main Authors:	Heckman, Pim R. A., van Duinen, Marlies A., Bollen, Eva P. P., Nishi, Akinori, Wennogle, Lawrence P., Blokland, Arjan, Prickaerts, Jos
Format:	Journal Article
Language:	English
Published:	US Oxford University Press 02-04-2016
Subjects:	Review phosphodiesterase cyclic adenosine monophosphate dopamine fronto-striatal circuits phosphodiesterase inhibitors
Online Access:	Get full text
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1461-1457 1469-5111
DOI:	10.1093/ijnp/pyw030