title: Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications.
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.
  
  
  CONCLUSIONS
  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.
authors.forename: Pim R A
authors.initials: PRA
authors.lastname: Heckman
authors.forename: Marlies A
authors.initials: MA
authors.lastname: van Duinen
authors.forename: Eva P P
authors.initials: EPP
authors.lastname: Bollen
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Wennogle
authors.forename: Arjan
authors.initials: A
authors.lastname: Blokland
authors.forename: Jos
authors.initials: J
authors.lastname: Prickaerts
keywords: cyclic adenosine monophosphate; dopamine; fronto-striatal circuits; phosphodiesterase; phosphodiesterase inhibitors