Recent advances in the neurobiology of alcoholism: the role of adenosine

Pharmacol Ther. 2004 Jan;101(1):39-46. doi: 10.1016/j.pharmthera.2003.10.002.


Neuronal responses to alcohol involve several hormone- and neurotransmitter-activated signal transduction pathways. Recent studies suggest that the adenosine A2 receptor (A2) mediates important actions of alcohol. Ethanol inhibits adenosine reuptake, increases extracellular adenosine, and promotes activation of A2. This leads to enhanced cAMP/protein kinase A (PKA) signaling ranging from increases in cAMP to stimulation of cAMP-dependent cAMP response element (CRE)-mediated gene expression. Medium spiny neurons in the striatum/nucleus accumbens (NAc) express A2 and dopamine D2 receptor (D2) on the same cells. Studies in model neuronal cell lines and primary neurons in culture expressing A2 and D2 provide evidence for synergy between ethanol/A2 and D2. Subthreshold concentrations of ethanol or a D2 agonist, without effect separately, synergistically activate cAMP/PKA signaling. Thus, neurons expressing A2 and D2 on the same cells, like in the NAc, are characterized by hypersensitivity to ethanol with a simultaneous activation of dopaminergic signaling. Synergy requires adenosine and appears to be mediated by the release of free betagamma dimers from G(i/o) via D2 activation. The release of free betagamma has pathophysiological significance in the drinking animal because specific blockade of betagamma signaling in the NAc strikingly reduces voluntary alcohol consumption. These findings suggest that signaling pathways, which regulate synergy between A2 and D2, might contain molecular targets for the prevention and treatment of alcoholism and alcohol abuse.

Publication types

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

MeSH terms

  • Adenosine / metabolism*
  • Alcoholism / metabolism*
  • Animals
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dimerization
  • Equilibrative Nucleoside Transporter 1 / metabolism
  • Ethanol / pharmacology
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Nucleus Accumbens / metabolism
  • Receptors, Adenosine A2 / metabolism
  • Receptors, Dopamine D2 / metabolism


  • Equilibrative Nucleoside Transporter 1
  • Receptors, Adenosine A2
  • Receptors, Dopamine D2
  • Ethanol
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Adenosine