Type 1 equilibrative nucleoside transporter regulates ethanol drinking through accumbal N-methyl-D-aspartate receptor signaling. Biol Psychiatry 2011 Jun 01;69(11):1043-51
Date
04/15/2011Pubmed ID
21489406Pubmed Central ID
PMC3090461DOI
10.1016/j.biopsych.2011.02.013Scopus ID
2-s2.0-79955772672 (requires institutional sign-in at Scopus site) 51 CitationsAbstract
BACKGROUND: Mice lacking type 1 equilibrative nucleoside transporter (ENT1(-/-)) exhibit increased ethanol-preferring behavior compared with wild-type littermates. This phenotype of ENT1(-/-) mice appears to be correlated with increased glutamate levels in the nucleus accumbens (NAc). However, little is known about the downstream consequences of increased glutamate signaling in the NAc.
METHODS: To investigate the significance of the deletion of ENT1 and its effect on glutamate signaling in the NAc, we employed microdialysis and iTRAQ proteomics. We validated altered proteins using Western blot analysis. We then examined the pharmacological effects of the inhibition of the N-methyl-D-aspartate (NMDA) glutamate receptor and protein kinase Cγ (PKCγ) on alcohol drinking in wild-type mice. In addition, we investigated in vivo cyclic adenosine monophosphate response element binding activity using cyclic adenosine monophosphate response element-β-galactosidase mice in an ENT1(-/-) background.
RESULTS: We identified that NMDA glutamate receptor-mediated downregulation of intracellular PKCγ-neurogranin-calcium-calmodulin dependent protein kinase type II signaling is correlated with reduced cyclic adenosine monophosphate response element binding activity in ENT1(-/-) mice. Inhibition of PKCγ promotes ethanol drinking in wild-type mice to levels similar to those of ENT1(-/-) mice. In contrast, an NMDA glutamate receptor antagonist reduces ethanol drinking of ENT1(-/-) mice.
CONCLUSIONS: These findings demonstrate that the genetic deletion or pharmacological inhibition of ENT1 regulates NMDA glutamate receptor-mediated signaling in the NAc, which provides a molecular basis that underlies the ethanol-preferring behavior of ENT1(-/-) mice.
Author List
Nam HW, Lee MR, Zhu Y, Wu J, Hinton DJ, Choi S, Kim T, Hammack N, Yin JC, Choi DSAuthor
Ryan M. Lee MD Instructor in the Neurology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
2-Amino-5-phosphonovalerateAlcohol Drinking
Analysis of Variance
Animals
Blotting, Western
Cyclic AMP Response Element-Binding Protein
Equilibrative Nucleoside Transporter 1
Ethanol
Excitatory Amino Acid Antagonists
Glutamic Acid
Male
Mice
Mice, Knockout
Microdialysis
Nucleus Accumbens
Protein Kinase C
Receptors, N-Methyl-D-Aspartate
Self Administration
Signal Transduction
