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The Journal of Neuroscience, May 26, 2004, 24(21):5022-5030; doi:10.1523/JNEUROSCI.5557-03.2004

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Behavioral/Systems/Cognitive
Partial Deletion of the cAMP Response Element-Binding Protein Gene Promotes Alcohol-Drinking Behaviors

Subhash C. Pandey, Adip Roy, Huaibo Zhang, and Tiejun Xu

Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago and Veterans Affairs Chicago Health Care System, Chicago, Illinois 60612

The cAMP response element-binding protein (CREB) gene transcription factor has been shown to play a role in the synaptic plasticity associated with drug addictive behaviors; however, the causal role of the CREB gene in alcohol-drinking behaviors is unknown. The present investigation evaluated alcohol-drinking behaviors in mice that are haplodeficient in CREB as a result of targeted CREB ( and ) gene disruption. It was found that CREB-haplodeficient (+/-) mice have higher preference for ethanol but not for sucrose solution than wild-type (+/+) littermates. The functional aspects of the CREB gene transcription factor were also investigated by measuring the protein levels of phosphorylated CREB (p-CREB) and the expression of cAMP-inducible genes such as neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF). Deletion of the CREB ( and ) gene significantly decreases total CREB, p-CREB levels and the expression of NPY and BDNF in the brain structures of CREB-deficient (+/-) mice. It was also found that CREB-deficient (+/-) mice displayed more anxiety-like behaviors and that acute ethanol exposure produced anxiolytic effects and significantly increased protein levels of p-CREB and NPY in the central and medial but not in the basolateral amygdala of wild-type mice, but these effects are attenuated in CREB-deficient mice compared with wild-type mice. These results provide the first direct evidence that a haplodeficiency of the CREB gene is associated with increased alcohol-drinking behaviors. Furthermore, alcohol drinking and anxiety-like behaviors in CREB-haplodeficient mice may possibly be related to decreased expression of NPY and BDNF in the brains of these mice.

Key words: CREB; NPY; BDNF; alcohol preference; anxiety; alcoholism

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Received Dec 17, 2003; revised March 30, 2004; accepted April 15, 2004.

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