betagamma Dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption

Cell. 2002 Jun 14;109(6):733-43. doi: 10.1016/s0092-8674(02)00763-8.

Abstract

Dopamine release is activated by ethanol and addicting drugs, but molecular mechanisms linking dopaminergic signaling to neuronal responses and drinking behavior are poorly understood. We report that dopamine-D2 receptors induce PKA Calpha translocation and increase CRE-regulated gene expression. Ethanol also activates PKA signaling. Subthreshold concentrations of the D2 agonist NPA and ethanol, without effect alone, together cause synergistic PKA translocation and CRE-mediated gene transcription. D2 or adenosine A2 receptor blockade, pertussis toxin, Rp-cAMPS, or overexpression of dominant-negative peptides that sequester betagamma dimers prevent synergy. Importantly, overexpression of a betagamma inhibitor peptide in the nucleus accumbens strikingly reduces sustained alcohol consumption. We propose that synergy of D2 and A2 confers ethanol hypersensitivity and that betagamma dimers are required for voluntary drinking.

Publication types

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

MeSH terms

  • Adenoviridae / genetics
  • Alcohol Drinking
  • Animals
  • Animals, Newborn
  • Apomorphine / analogs & derivatives*
  • Apomorphine / pharmacology
  • Blotting, Western
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Dimerization
  • Dopamine Agonists / pharmacology
  • Dose-Response Relationship, Drug
  • Ethanol / pharmacology*
  • G1 Phase
  • Gene Expression Regulation
  • Genes, Reporter
  • Hippocampus / cytology
  • Immunohistochemistry
  • Integrases / metabolism
  • Isoenzymes / metabolism
  • Luciferases / metabolism
  • Microscopy, Confocal
  • Models, Biological
  • Peptides / chemistry
  • Pertussis Toxin
  • Protein Binding
  • Protein Kinase C / metabolism
  • Protein Kinase C-alpha
  • Protein Structure, Tertiary
  • Protein Transport
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / chemistry
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Purinergic P1 / chemistry
  • Receptors, Purinergic P1 / metabolism*
  • Signal Transduction
  • Subcellular Fractions
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Viral Proteins / metabolism
  • Virulence Factors, Bordetella / pharmacology

Substances

  • 10,11-dihydroxy-N-n-propylnorapomorphine
  • Dopamine Agonists
  • Isoenzymes
  • Peptides
  • Receptors, Dopamine D2
  • Receptors, Purinergic P1
  • Viral Proteins
  • Virulence Factors, Bordetella
  • Ethanol
  • Cyclic AMP
  • Luciferases
  • Pertussis Toxin
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Cre recombinase
  • Integrases
  • Apomorphine