Abstract
Three distinct classes of drugs: dopaminergic agonists (such as D-amphetamine), serotonergic agonists (such as LSD), and glutamatergic antagonists (such as PCP) all induce psychotomimetic states in experimental animals that closely resemble schizophrenia symptoms in humans. Here we implicate a common signaling pathway in mediating these effects. In this pathway, dopamine- and an adenosine 3',5'-monophosphate (cAMP)-regulated phospho-protein of 32 kilodaltons (DARPP-32) is phosphorylated or dephosphorylated at three sites, in a pattern predicted to cause a synergistic inhibition of protein phosphatase-1 and concomitant regulation of its downstream effector proteins glycogen synthesis kinase-3 (GSK-3), cAMP response element-binding protein (CREB), and c-Fos. In mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32, the effects of D-amphetamine, LSD, and PCP on two behavioral parameters-sensorimotor gating and repetitive movements-were strongly attenuated.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
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Animals
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Brain / drug effects
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Brain / metabolism*
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Central Nervous System Agents / pharmacology*
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Dextroamphetamine / pharmacology
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Dopamine / metabolism
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Dopamine and cAMP-Regulated Phosphoprotein 32
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Frontal Lobe / drug effects
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Frontal Lobe / metabolism
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Genes, fos
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Lysergic Acid Diethylamide / pharmacology
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Male
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Mice
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Mice, Knockout
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Motor Activity / drug effects
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Nerve Tissue Proteins / metabolism
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Phencyclidine / pharmacology
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Phosphoproteins / metabolism*
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Phosphorylation
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Protein Phosphatase 1
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Dopamine D1 / genetics
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Receptors, Dopamine D1 / metabolism
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Reflex, Startle / drug effects
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Signal Transduction*
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Synaptic Transmission
Substances
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Central Nervous System Agents
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Cyclic AMP Response Element-Binding Protein
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Dopamine and cAMP-Regulated Phosphoprotein 32
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Nerve Tissue Proteins
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Phosphoproteins
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RNA, Messenger
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Receptors, Dopamine D1
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Lysergic Acid Diethylamide
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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Phencyclidine
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Dextroamphetamine
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Dopamine