The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference

Nat Neurosci. 2004 Aug;7(8):855-61. doi: 10.1038/nn1288. Epub 2004 Jul 18.


Adenosine is an important mediator of ethanol intoxication. In vitro, ethanol stimulates adenosine signaling by inhibiting the type 1 equilibrative nucleoside transporter (ENT1), whereas chronic ethanol exposure downregulates ENT1. It is not known, however, whether ENT1 is important for ethanol intoxication or consumption in vivo. Here we report that ENT1-null mice show reduced hypnotic and ataxic responses to ethanol and greater consumption of alcohol as compared with their wild-type littermates. These features are associated with a decrease in adenosine tone, as measured indirectly as a reduction in A(1) receptor-mediated inhibition of glutamate excitatory postsynaptic currents (EPSCs) in the nucleus accumbens, leading to increased phosphorylation of CRE-binding protein (CREB) in the striatum. Treatment with an A(1) receptor agonist decreases EPSC amplitude and reduces ethanol consumption in ENT1-null mice. Our results indicate that ENT1 has a physiological role in ethanol-mediated behaviors and suggest that decreased A(1) adenosine receptor function promotes alcohol consumption.

Publication types

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

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Adenosine / pharmacology
  • Alcohol Drinking / metabolism*
  • Alcoholic Intoxication / metabolism*
  • Alcoholism / genetics
  • Animals
  • Corpus Striatum / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Equilibrative Nucleoside Transporter 1 / genetics
  • Equilibrative Nucleoside Transporter 1 / metabolism*
  • Excitatory Postsynaptic Potentials / physiology
  • Genetic Predisposition to Disease
  • Male
  • Mice
  • Nucleus Accumbens / metabolism*
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Phosphorylation
  • Receptors, Purinergic P1 / metabolism


  • Cyclic AMP Response Element-Binding Protein
  • Equilibrative Nucleoside Transporter 1
  • Receptors, Purinergic P1
  • N(6)-cyclopentyladenosine
  • Adenosine