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Regulation of dopamine signaling in the striatum by phosphodiesterase inhibitors: novel therapeutics to treat neurological and psychiatric disorders.

Abnormal dopamine neurotransmission has been linked to a wide array of motor, cognitive, and psychiatric disorders. Dopamine binds and regulates intracellular signals through D1-like (D1 and D5) and D2-like (D2, D3, and D4) G-protein coupled receptors. Activation of D1- like receptors stimulates cAMP/PKA signaling via Gs mediated activation of adenylyl cyclase. In contrast, activation of D2-like receptors inhibits cAMP/PKA signaling by Gi inhibition of adenylyl cyclase. In the brain, dopamine signaling is tightly regulated by cyclic nucleotide phosphodiesterases (PDEs). PDEs are a family of enzymes that selectively degrade cAMP and cGMP. There are 11 different families of PDEs that vary in their substrate specificity, kinetic properties, mode of regulation, intracellular localization, and tissue expression patterns. A number of PDE families are highly expressed in the striatum including PDE1, PDE2, PDE4, and PDE10. There is a growing amount of evidence to suggest that these enzymes play a critical role in modulating dopamine signaling and selective inhibitors of these enzymes are currently being explored as novel therapeutics to treat schizophrenia, Huntington's disease, cognitive disorders and Parkinson's disease. The aim of this review is to summarize the distinct roles of different PDEs in regulating dopamine signaling in the striatum. In addition, we will briefly review the therapeutic potential of selective PDE inhibitors to treat neurological and psychiatric disorders associated with abnormal striatal function.