Ethanol inhibits the type 1 equilibrative nucleoside transporter (ENT1) in cultured cells. Preliminary studies with ENT1 null mice indicate that ENT1 is also a target for ethanol in vivo since ENT1 null mice are less responsive to acute effects of ethanol. ENT1 null mice also consume more ethanol than wild type littermates. Preliminary studies demonstrate that glutamate-driven CREB activation was increased in the striatum of ENT1 null mice. This appears to result from diminished activation of striatal presynaptic adenosine A1 receptors due to reduced adenosine tone as measured by electrophysiological studies. Since striatal CREB activation is associated with reduced drug reward, excessive ethanol drinking in ENT1 null mice may be causally related to tolerance to ethanol reward. Consistent with this hypothesis, a conditioned place preference study demonstrated that ENT1 null mice prefer the ethanol-paired side(2.0 g/kg) significantly less than wild type mice. This proposal will expand upon preliminary studies and examine the role of CREB signaling in regulating behavioral responses to alcohol in ENT1 null mice. First, initial sensitivity, acute and chronic tolerance, operant self-administration, and place conditioning assays will be used to examine ethanol tolerance, and rewarding and reinforcing effects of ethanol. Second, increases in CREB activity will be identified in specific cells using CRE-lacZ reporter mice and by examining expression of two CRE-driven genes, enkephalin and dynorphin, in the striatum of ENT1 null mice. Third, pCREB immunoreactivity will be used to measure CREB activity in striatal brain slices to identify signaling pathways that contribute to increased basal CREB activity in ENT1 null mice. Finally, we will determine whether alterations in signaling pathways that account for increased striatal pCREB contribute to tolerance to rewarding effects of ethanol and increased ethanol consumption in ENT1 null mice. The goal of this project is to understand signaling pathways underlying enhanced alcohol drinking behavior in ENT1 null mice and to identify novel therapeutic targets for alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015164-05
Application #
7778372
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Baizer, Lawrence
Project Start
2006-03-20
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$256,087
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Nam, Hyung Wook; Hinton, David J; Kang, Na Young et al. (2013) Adenosine transporter ENT1 regulates the acquisition of goal-directed behavior and ethanol drinking through A2A receptor in the dorsomedial striatum. J Neurosci 33:4329-38
Nam, Hyung Wook; Bruner, Robert C; Choi, Doo-Sup (2013) Adenosine signaling in striatal circuits and alcohol use disorders. Mol Cells 36:195-202
Moss, Aaron M; Endres, Christopher J; Ruiz-Garcia, Ana et al. (2012) Role of the equilibrative and concentrative nucleoside transporters in the intestinal absorption of the nucleoside drug, ribavirin, in wild-type and Ent1(-/-) mice. Mol Pharm 9:2442-9
Wu, Jinhua; Lee, Moonnoh R; Kim, Taehyun et al. (2011) Regulation of ethanol-sensitive EAAT2 expression through adenosine A1 receptor in astrocytes. Biochem Biophys Res Commun 406:47-52
Nam, Hyung Wook; Lee, Moonnoh R; Zhu, Yu et al. (2011) Type 1 equilibrative nucleoside transporter regulates ethanol drinking through accumbal N-methyl-D-aspartate receptor signaling. Biol Psychiatry 69:1043-51
Asatryan, Liana; Nam, Hyung W; Lee, Moonnoh R et al. (2011) Implication of the purinergic system in alcohol use disorders. Alcohol Clin Exp Res 35:584-94
Lee, Moonnoh R; Hinton, David J; Wu, Jinhua et al. (2011) Acamprosate reduces ethanol drinking behaviors and alters the metabolite profile in mice lacking ENT1. Neurosci Lett 490:90-5
Lee, Moonnoh R; Hinton, David J; Unal, Sencan S et al. (2011) Increased ethanol consumption and preference in mice lacking neurotensin receptor type 2. Alcohol Clin Exp Res 35:99-107
Kim, Jeong-Hyun; Karpyak, Victor M; Biernacka, Joanna M et al. (2011) Functional role of the polymorphic 647 T/C variant of ENT1 (SLC29A1) and its association with alcohol withdrawal seizures. PLoS One 6:e16331

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