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

被引:44
作者
Heckman, Pim R. A. [1 ,2 ]
van Duinen, Marlies A. [1 ]
Bollen, Eva P. P. [1 ]
Nishi, Akinori [3 ]
Wennogle, Lawrence P. [4 ]
Blokland, Arjan [2 ]
Prickaerts, Jos [1 ]
机构
[1] Maastricht Univ, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, NL-6200 MD Maastricht, Netherlands
[2] Maastricht Univ, Dept Neuropsychol & Psychopharmacol, Maastricht, Netherlands
[3] Kurume Univ, Sch Med, Dept Pharmacol, Kurume, Fukuoka, Japan
[4] Intracellular Therapies Inc, New York, NY USA
关键词
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;
D O I
10.1093/ijnp/pyw030
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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. Clinical studies of the effects of different phosphodiesterase inhibitors on cognition, affect, and motor function in relation to the fronto-striatal circuits are reviewed. Several selective phosphodiesterase inhibitors have positive effects on cognition, affect, and motor function in relation to the fronto-striatal circuits. 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.
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页码:1 / 16
页数:16
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