Potential for targeting dopamine/DARPP-32 signaling in neuropsychiatric and neurodegenerative disorders. (4th March 2017)

• Record Type: Journal Article
• Authors: Nishi, Akinori; Shuto, Takahide
• Is Part Of: Expert opinion on therapeutic targets. Volume 21:Number 3(2017:Mar.)
• Page Start: 259
• Page End: 272
• Publication Date: 2017-03-04
• Subjects: DARPP-32 -- dopamine -- drug addiction -- D1 receptor -- D2 receptor; Drugs -- Research -- Periodicals; 615.072
• DOI: 10.1080/14728222.2017.1279149
• Languages: English
• ISSNs: 1744-7631

Abstract

ABSTRACT: Introduction: Alterations in dopamine neurotransmission has been implicated in pathophysiology of neuropsychiatric and neurodegenerative disorders, and DARPP-32 plays a pivotal role in dopamine neurotransmission. DARPP-32 likely influences dopamine-mediated behaviors in animal models of neuropsychiatric and neurodegenerative disorders and therapeutic effects of pharmacological treatment. Areas covered: We will review animal studies on the biochemical and behavioral roles of DARPP-32 in drug addiction, schizophrenia and Parkinson's disease. In general, under physiological and pathophysiological conditions, DARPP-32 in D1 receptor expressing (D1R) -medium spiny neurons (MSNs) promotes dopamine/D1 receptor/PKA signaling, whereas DARPP-32 in D2 receptor expressing (D2R)-MSNs counteracts dopamine/D2 receptor signaling. However, the function of DARPP-32 is differentially regulated in acute and chronic phases of drug addiction; DARPP-32 enhances D1 receptor/PKA signaling in the acute phase, whereas DARPP-32 suppresses D1 receptor/PKA signaling in the chronic phase through homeostatic mechanisms. Therefore, DARPP-32 plays a bidirectional role in dopamine neurotransmission, depending on the cell type and experimental conditions, and is involved in dopamine-related behavioral abnormalities. Expert opinion: DARPP-32 differentially regulates dopamine signaling in D1R- and D2R-MSNs, and a shift of balance between D1R- and D2R-MSN function is associated with behavioral abnormalities. An adjustment of this imbalance is achieved by therapeutic approaches targeting DARPP-32-related signaling molecules.