CREB, Alcohol Reward and Consumption in ENT1 Null Mice

Project: Research project

Project Details


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.
StatusNot started


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