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The Journal of Neuroscience, March 5, 2008, 28(10):2589-2600; doi:10.1523/JNEUROSCI.4752-07.2008

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Behavioral/Systems/Cognitive
Effector Immediate-Early Gene Arc in the Amygdala Plays a Critical Role in Alcoholism

Subhash C. Pandey,^1,2,3 Huaibo Zhang,^1,3 Rajesh Ugale,^1,3 Anand Prakash,^1,3 Tiejun Xu,^1,3 and Kaushik Misra^1,3

Departments of ¹Psychiatry and ²Anatomy and Cell Biology, University of Illinois at Chicago, and ³Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612

Correspondence should be addressed to Dr. Subhash C. Pandey, Department of Psychiatry, University of Illinois at Chicago, and Jesse Brown Veterans Administration Medical Center, 820 South Damen Avenue (M/C 151), Chicago, IL 60612. Email: scpandey{at}uic.edu

The immediate early gene, activity-regulated cytoskeleton-associated protein (Arc), has been implicated in synaptic plasticity. However, the role of Arc in alcoholism is unknown. Here, we report that the anxiolytic effects of acute ethanol were associated with increased brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (trkB) expression, increased phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2), Elk-1, and cAMP responsive element-binding protein (CREB), increased Arc expression, and increased dendritic spine density (DSD) in both the central amygdala (CeA) and medial amygdala (MeA) but not in the basolateral amygdala (BLA) of rats. Conversely, the anxiogenic effects of withdrawal after long-term ethanol exposure were associated with decreased BDNF and trkB expression, decreased phosphorylation of Erk1/2, Elk-1, and CREB, decreased Arc expression, and decreased DSD in both the CeA and MeA but not in the BLA of rats. We also showed that BDNF infusion into the CeA normalized phosphorylation of Erk1/2, Elk-1, and CREB, and normalized Arc expression, thereby protecting against the onset of ethanol withdrawal-related anxiety. We further demonstrated that arresting Arc expression in the CeA decreased DSD, thereby increasing anxiety-like and alcohol-drinking behaviors in control rats. These results revealed that BDNF–Arc signaling and the associated DSD in the CeA, and possibly in the MeA, may be involved in the molecular processes of alcohol dependence and comorbidity of anxiety and alcohol-drinking behaviors.

Key words: Arc; BDNF; amygdala; anxiety; alcoholism; dendritic spines

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Received May 17, 2007; revised Jan. 15, 2008; accepted Jan. 18, 2008.

Correspondence should be addressed to Dr. Subhash C. Pandey, Department of Psychiatry, University of Illinois at Chicago, and Jesse Brown Veterans Administration Medical Center, 820 South Damen Avenue (M/C 151), Chicago, IL 60612. Email: scpandey{at}uic.edu

This article has been cited by other articles:

				J. Jeanblanc, D.-Y. He, S. Carnicella, V. Kharazia, P. H. Janak, and D. Ron Endogenous BDNF in the Dorsolateral Striatum Gates Alcohol Drinking J. Neurosci., October 28, 2009; 29(43): 13494 - 13502. [Abstract] [Full Text] [PDF]

				S. C. Pandey, R. Ugale, H. Zhang, L. Tang, and A. Prakash Brain Chromatin Remodeling: A Novel Mechanism of Alcoholism J. Neurosci., April 2, 2008; 28(14): 3729 - 3737. [Abstract] [Full Text] [PDF]

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