Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice

Neuron. 2003 Apr 24;38(2):291-303. doi: 10.1016/s0896-6273(03)00192-2.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Behavior, Animal / drug effects
  • Binding, Competitive / genetics
  • Central Nervous System Stimulants / pharmacology*
  • Cocaine / pharmacology
  • Corpus Striatum / cytology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dopamine / metabolism*
  • Dopamine Agonists / pharmacology*
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Dose-Response Relationship, Drug
  • G-Protein-Coupled Receptor Kinases
  • Gene Targeting
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Motor Activity / drug effects*
  • Motor Activity / physiology
  • Nerve Tissue Proteins*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Phenethylamines / pharmacology
  • Phosphoproteins / biosynthesis
  • Protein-Serine-Threonine Kinases / deficiency*
  • Protein-Serine-Threonine Kinases / genetics
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism

Substances

  • Central Nervous System Stimulants
  • Dopamine Agonists
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Nerve Tissue Proteins
  • Phenethylamines
  • Phosphoproteins
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • phenethylamine
  • Amphetamine
  • Protein-Serine-Threonine Kinases
  • G-Protein-Coupled Receptor Kinases
  • G-protein-coupled receptor kinase 6
  • Cocaine
  • Dopamine