The treatment of alcoholism requires the proper management of ethanol withdrawal symptoms, such as anxiety, to prevent further alcohol use and abuse. In this study, we investigated the potential role of brain chromatin remodeling, caused by histone modifications, in alcoholism. We found that the anxiolytic effects produced by acute alcohol were associated with a decrease in histone deacetylase (HDAC) activity and increases in acetylation of histones (H3 and H4), levels of CREB (cAMP-responsive element binding) binding protein (CBP), and neuropeptide Y (NPY) expression in the amygdaloid brain regions of rats. However, the anxiety-like behaviors during withdrawal after chronic alcohol exposure were associated with an increase in HDAC activity and decreases in acetylation of H3 and H4, and levels of both CBP and NPY in the amygdala. Blocking the observed increase in HDAC activity during alcohol withdrawal with the HDAC inhibitor, trichostatin A, rescued the deficits in H3 and H4 acetylation and NPY expression (mRNA and protein levels) in the amygdala (central and medial nucleus of amygdala) and prevented the development of alcohol withdrawal-related anxiety in rats as measured by the elevated plus maze and light/dark box exploration tests. These results reveal a novel role for amygdaloid chromatin remodeling in the process of alcohol addiction and further suggest that HDAC inhibitors may be potential therapeutic agents in treating alcohol withdrawal symptoms.

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.

Background: The neuropeptide Y (NPY) system of the central nucleus of amygdala (CeA) has been shown to be involved in anxiety and alcoholism. In this study, we investigated the molecular mechanisms by which NPY in the CeA regulates anxiety and alcohol drinking behaviors using alcohol-preferring (P) rats as an animal model.

Our results demonstrated the contributory role of neuroactive steroid 3alpha, 5alpha-THP in the anti-anxiety effect of ethanol. It is speculated that ethanol-induced modulation of endogenous GABAergic neurosteroids, especially 3alpha, 5alpha-THP, might be crucial pertinent to the etiology of 'trait' anxiety (tension reduction) and ethanol abuse.

Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2C-containing NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition. Specifically, pyramidal neurons in the medial prefrontal cortex (mPFC) of GluN2C knockout mice have reduced mEPSC frequency and dendritic spine density and a contrasting higher frequency of mIPSCs. In addition a greater number of perisomatic GAD67 puncta was observed suggesting a potential increase in parvalbumin interneuron inputs. At a network level the GluN2C knockout mice were found to have a more robust increase in power of oscillations in response to NMDAR blocker MK-801. Furthermore, GluN2C heterozygous and knockout mice exhibited abnormalities in cognition and sensorimotor gating. Our results demonstrate that loss of GluN2C subunit leads to cortical excitatory-inhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders.