Effector Immediate-Early Gene Arc in the Amygdala Plays a Critical Role in Alcoholism

Abstract

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 signalregulated 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.

Brain Chromatin Remodeling: A Novel Mechanism of Alcoholism

“…We reported previously that acute ethanol increased CREB phosphorylation in the CeA and MeA but not in BLA of rats and mice (Pandey et al, , 2005(Pandey et al, , 2008. Conversely, ethanol withdrawal after chronic ethanol exposure decreased CREB phosphorylation, but not total CREB protein levels, in the CeA and MeA of rats (Pandey et al, , 2008. Combining these findings with our current findings on CBP suggests the possibility that decreased functioning of CREB may lead to decreased HAT activity (decreased CBP levels), which may attenuate the acetylation states of histones H3 and H4 in the amygdala during ethanol withdrawal.…”

“…Furthermore, mutations in the CBP gene produced RubinsteinTaybi syndrome in humans, characterized by severe mental retardation and abnormal gross anatomy (Rubinstein and Taybi, 1963;Hennekam et al, 1992;Petrij et al, 1995). We reported previously that acute ethanol increased CREB phosphorylation in the CeA and MeA but not in BLA of rats and mice (Pandey et al, , 2005(Pandey et al, , 2008. Conversely, ethanol withdrawal after chronic ethanol exposure decreased CREB phosphorylation, but not total CREB protein levels, in the CeA and MeA of rats (Pandey et al, , 2008.…”

“…The cessation of chronic ethanol consumption has been shown to lead to the development of withdrawal symptoms both in human alcoholics and animal models (Weiss and Rosenberg, 1985;Wilson, 1988;Lal et al, 1993;Rassnick et al, 1993;Koob, 2003;Pandey, 2003;Pandey et al, 2003Pandey et al, , 2008. Anxiety-like behaviors, which appear during the early phase of withdrawal, play crucial roles in the maintenance of alcohol drinking behaviors in both humans and animals (Hershon, 1977;Wilson, 1988;Koob, 2003;Pandey, 2003;Funk et al, 2006).…”

“…Male adult Sprague Dawley rats were housed individually and offered 80 ml of the nutritionally complete Lieber-DeCarli control diet (Lieber-DeCarli Diet 82; Bio-Serv, Frenchtown, NJ) as their source of food and fluid. Rats were fed with the Lieber-DeCarli ethanol and control-diets, as described previously by us (Pandey et al, 1999(Pandey et al, , 2001(Pandey et al, , 2008. One group of rats was gradually habituated to ethanol (within 7 d) and maintained on the ethanolcontaining (9% v/v) Lieber-DeCarli liquid diet for 15 or 16 d (ethanol diet-fed group).…”

Neurochemical and Neurostructural Plasticity in Alcoholism

“…125 Interestingly, these behavioral changes were reversed when BDNF was infused into the CeA. 125 The results of these studies should be interpreted with caution since extraneous factors such as alcohol-induced nutritional insufficiency and neuronal cell death can influence dendritic spine morphology. 97,98 Nonetheless, it appears that several factors, such as the timing of alcohol exposure as well as the brain region involved, are critical in determining the specific influence of alcohol exposure on dendritic spines.…”