title: The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference.
abstract: 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.
authors.affiliation: Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California, 94608, USA.
authors.forename: Doo-Sup
authors.initials: DS
authors.lastname: Choi
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Cascini
authors.forename: William
authors.initials: W
authors.lastname: Mailliard
authors.forename: Hannah
authors.initials: H
authors.lastname: Young
authors.forename: Peter
authors.initials: P
authors.lastname: Paredes
authors.forename: Thomas
authors.initials: T
authors.lastname: McMahon
authors.forename: Ivan
authors.initials: I
authors.lastname: Diamond
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
authors.forename: Robert O
authors.initials: RO
authors.lastname: Messing
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000428:Alcohol Drinking / Q000378:metabolism*; D000435:Alcoholic Intoxication / Q000378:metabolism*; D000437:Alcoholism / Q000235:genetics; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D009714:Nucleus Accumbens / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D018047:Receptors, Purinergic P1 / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D033721:Equilibrative Nucleoside Transporter 1; D018047:Receptors, Purinergic P1; C048599:N(6)-cyclopentyladenosine; D000241:Adenosine