Effector Immediate-Early Gene Arc in the Amygdala Plays a Critical Role in Alcoholism
The Journal of Neuroscience, March 5, 2008, 28(10):2589-2600
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.
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