title: Potential for targeting dopamine/DARPP-32 signaling in neuropsychiatric and neurodegenerative disorders.
abstract: 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.
authors.affiliation: a Department of Pharmacology , Kurume University School of Medicine , Kurume, Fukuoka , Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
authors.affiliation: a Department of Pharmacology , Kurume University School of Medicine , Kurume, Fukuoka , Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Shuto
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy* / Q000503:physiopathology; D058990:Molecular Targeted Therapy; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000503:physiopathology; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497928:PPP1R1B protein, human; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D004298:Dopamine
keywords: D1 receptor; D2 receptor; DARPP-32; dopamine; drug addiction