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

Lina Yao, Maria Pia Arolfo, Douglas P. Dohrman, Zhan Jiang, Peidong Fan, Sara Fuchs, Patricia H. Janak, Adrienne S. Gordon, Ivan Diamond

Research output: Contribution to journalArticlepeer-review

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 Cα 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 βγ dimers prevent synergy. Importantly, overexpression of a βγ inhibitor peptide in the nucleus accumbens strikingly reduces sustained alcohol consumption. We propose that synergy of D2 and A2 confers ethanol hypersensitivity and that βγ dimers are required for voluntary drinking.

Original languageEnglish (US)
Pages (from-to)733-743
Number of pages11
JournalCell
Volume109
Issue number6
DOIs
StatePublished - Jun 14 2002
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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