title: Striatal adenosine signaling regulates EAAT2 and astrocytic AQP4 expression and alcohol drinking in mice.
abstract: Adenosine signaling is implicated in several neuropsychiatric disorders, including alcoholism. Among its diverse functions in the brain, adenosine regulates glutamate release and has an essential role in ethanol sensitivity and preference. However, the molecular mechanisms underlying adenosine-mediated glutamate signaling in neuroglial interaction remain elusive. We have previously shown that mice lacking the ethanol-sensitive adenosine transporter, type 1 equilibrative nucleoside transporter (ENT1), drink more ethanol compared with wild-type mice and have elevated striatal glutamate levels. In addition, ENT1 inhibition or knockdown reduces glutamate transporter expression in cultured astrocytes. Here, we examined how adenosine signaling in astrocytes contributes to ethanol drinking. Inhibition or deletion of ENT1 reduced the expression of type 2 excitatory amino-acid transporter (EAAT2) and the astrocyte-specific water channel, aquaporin 4 (AQP4). EAAT2 and AQP4 colocalization was also reduced in the striatum of ENT1 null mice. Ceftriaxone, an antibiotic compound known to increase EAAT2 expression and function, elevated not only EAAT2 but also AQP4 expression in the striatum. Furthermore, ceftriaxone reduced ethanol drinking, suggesting that ENT1-mediated downregulation of EAAT2 and AQP4 expression contributes to excessive ethanol consumption in our mouse model. Overall, our findings indicate that adenosine signaling regulates EAAT2 and astrocytic AQP4 expressions, which control ethanol drinking in mice.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Moonnoh R
authors.initials: MR
authors.lastname: Lee
authors.forename: Christina L
authors.initials: CL
authors.lastname: Ruby
authors.forename: David J
authors.initials: DJ
authors.lastname: Hinton
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.forename: Chelsea A
authors.initials: CA
authors.lastname: Adams
authors.forename: Na
authors.initials: N
authors.lastname: Young Kang
authors.forename: Doo-Sup
authors.initials: DS
authors.lastname: Choi
mesh_terms: D000241:Adenosine / Q000502:physiology*; D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D051401:Aquaporin 4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001253:Astrocytes / Q000473:pathology / Q000502:physiology*; D002460:Cell Line; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D015536:Down-Regulation / Q000235:genetics; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D027342:Excitatory Amino Acid Transporter 2; C493396:Slc1a2 protein, mouse; D000241:Adenosine