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The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference

Nature Neuroscience volume 7, pages 855–861 (2004)Cite this article

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 A1 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 A1 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 A1 adenosine receptor function promotes alcohol consumption.

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Figure 1: Generation of ENT1-null mice.
Figure 2: Decreased acute alcohol responses in ENT1-null mice.
Figure 3: Increased alcohol preference in ENT1-null (−/−) mice.
Figure 4: Decreased A1 receptor modulation of striatal glutamate release in ENT1-null mice.
Figure 5: CREB phosphorylation is increased in the striatum of ENT1-null mice.
Figure 6: N6-CPA reduces ethanol self-administration in ENT1-null mice.

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Acknowledgements

We are grateful to S. Taylor and J. Connolly for technical support. This work was supported by funds provided by the State of California for medical research on alcohol and substance abuse through the University of California at San Francisco, and by the National Institute on Alcohol Abuse and Alcoholism (grant AA013588 to R.O.M.).

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  1. Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, 94608, California, USA

    Doo-Sup Choi, Maria-Grazia Cascini, William Mailliard, Hannah Young, Peter Paredes, Thomas McMahon, Ivan Diamond, Antonello Bonci & Robert O Messing

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Correspondence to Robert O Messing.

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Choi, DS., Cascini, MG., Mailliard, W. et al. The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat Neurosci 7, 855–861 (2004). https://doi.org/10.1038/nn1288

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