Abstract
Brain dopaminergic transmission is a critical component in numerous vital functions, and its dysfunction is involved in several disorders, including addiction and Parkinson's disease. Responses to dopamine are mediated via G protein-coupled dopamine receptors (D1-D5). Desensitization of G protein-coupled receptors is mediated via phosphorylation by members of the family of G protein-coupled receptor kinases (GRK1-GRK7). Here we show that GRK6-deficient mice are supersensitive to the locomotor-stimulating effect of psychostimulants, including cocaine and amphetamine. In addition, these mice demonstrate an enhanced coupling of striatal D2-like dopamine receptors to G proteins and augmented locomotor response to direct dopamine agonists both in intact and in dopamine-depleted animals. The present study indicates that postsynaptic D2-like dopamine receptors are physiological targets for GRK6 and suggests that this regulatory mechanism contributes to central dopaminergic supersensitivity.
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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Amphetamine / pharmacology
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Animals
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Behavior, Animal / drug effects
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Binding, Competitive / genetics
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Central Nervous System Stimulants / pharmacology*
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Cocaine / pharmacology
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Corpus Striatum / cytology
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Dopamine / metabolism*
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Dopamine Agonists / pharmacology*
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Dopamine and cAMP-Regulated Phosphoprotein 32
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Dose-Response Relationship, Drug
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G-Protein-Coupled Receptor Kinases
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Gene Targeting
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Mice
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Mice, Knockout
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Mice, Mutant Strains
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Motor Activity / drug effects*
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Motor Activity / physiology
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Nerve Tissue Proteins*
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism
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Phenethylamines / pharmacology
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Phosphoproteins / biosynthesis
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Protein Serine-Threonine Kinases / deficiency*
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Protein Serine-Threonine Kinases / genetics
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Receptors, Dopamine D1 / agonists
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Receptors, Dopamine D1 / metabolism
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Receptors, Dopamine D2 / agonists
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Receptors, Dopamine D2 / metabolism
Substances
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Central Nervous System Stimulants
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Dopamine Agonists
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Dopamine and cAMP-Regulated Phosphoprotein 32
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Nerve Tissue Proteins
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Phenethylamines
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Phosphoproteins
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Receptors, Dopamine D1
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Receptors, Dopamine D2
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phenethylamine
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Amphetamine
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Protein Serine-Threonine Kinases
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G-Protein-Coupled Receptor Kinases
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G-protein-coupled receptor kinase 6
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Cocaine
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Dopamine