Researchers led by Catherine Fortier at Harvard Medical School found that chronic alcohol misuse damaged white matter in areas of the brain that are important for self-control and recovery from alcoholism. The findings appeared in the December 2014 issue of Alcoholism: Clinical & Experimental Research.
Using high-resolution diffusion magnetic resonance brain scans, the researchers compared a group of 20 healthy light drinkers to a group of 31 individuals with a history of alcoholism. The recovering alcoholics drank heavily for an average of 25 years and had been sober for about five years.
Compared with the light drinkers, the abstinent alcoholics showed pronounced reductions in the structural integrity of frontal and superior white matter tracts. According to the authors, the results suggest altered connectivity in frontostriatal circuits—pathways associated with the amygdala, hippocampus, nucleus accumbens, regions that are involved in the brain’s reward system. These networks are essential for controlling impulsive behavior and stopping drinking.
The study also found that longer and heavier alcohol abuse was associated with greater damage. The findings pointed to possible recovery of white matter tissue in drinkers who became abstinent before they turned 50 years of age.
The authors recommend that future investigations should continue to explore white matter changes due to alcohol misuse, including measurements related to the severity of alcoholism and questions about tissue recovery with maintained abstinence.
Image Caption: Brain images from the study; used with permission. Credit: Dr. Catherine Fortier, Harvard Medical School.
Adapted from the story published in the NIAAA Spectrum, February 2015, Volume 7, Issue 1.
Results from a recent NIAAA study suggest that the medication ibudilast may be viable as a potential treatment for alcohol dependence. Ibudilast, an anti-inflammatory medication that acts as a non-selective phosphodiesterase inhibitor, reduces alcohol drinking and relapse in alcohol-preferring P rats, high-alcohol drinking HAD1 rats, and in mice made dependent on alcohol through cycles of alcohol vapor exposure.
Neuroinflammatory signaling pathways in the central nervous system are of current interest as potential pharmacotherapy targets for alcohol dependence. When administered twice daily, ibudilast reduced alcohol drinking in rats by approximately 50% and reduced drinking by alcohol-dependent mice at doses which had no effect in non-dependent mice.
Alcohol produces a wide range of pharmacological effects on the nervous system through its actions on ion channels. The molecular mechanism underlying ethanol modulation of ion channels is poorly understood. NIAAA scientists used a unique method of alcohol-tagging to demonstrate that alcohol activation of a G-protein-gated inwardly rectifying potassium (GIRK or Kir3) channel is mediated by a defined alcohol pocket through changes in affinity for the membrane phospholipid signaling molecule phosphatidylinositol 4,5-bisphosphate.
Surprisingly, hydrophobicity and size, but not the canonical hydroxyl, were important determinants of alcohol-dependent activation. Altering levels of G protein Gβγ subunits, conversely, did not affect alcohol-dependent activation, suggesting a fundamental distinction between receptor and alcohol gating of GIRK channels. The chemical properties of the alcohol pocket revealed here might extend to other alcohol-sensitive proteins, revealing a unique protein microdomain for targeting alcohol-selective therapeutics in the treatment of alcoholism and addiction. Understanding this mechanism will be critical for developing alcohol-selective therapeutics that can perhaps prevent alcohol abuse and treat addiction.
A recent NIAAA study determined the expression profile of microRNAs (miRNAs) in the nucleus accumbens (NAc) of rats treated with alcohol. MicroRNAs are non-coding RNA molecules thought to play a key role in and the regulation of gene expression. The study results suggest that multiple miRNAs were aberrantly expressed in rat NAc after alcohol injection. Among them, miR-382 was down-regulated in alcohol-treated rats.
In both cultured neuronal cells in vitro and in the NAc in vivo, researchers identified that the dopamine receptor D1 (Drd1) is a direct target gene of miR-382. Via this target gene, miR-382 strongly modulated the expression of DeltaFosB. Moreover, overexpression of miR-382 significantly attenuated alcohol-induced up-regulation of DRD1 and DeltaFosB, decreased voluntary intake of and preference for alcohol and inhibited the DRD1-induced action potential responses. The results indicate that miRNAs are involved in and may represent novel therapeutic targets for alcoholism.
The working hypothesis to explain the progression from mild (fatty liver) to more severe forms of alcoholic liver disease (e.g., fibrosis, cirrhosis, alcoholic hepatitis and hepatocellular carcinoma) has been that alcohol requires a secondary initiator or trigger for this progression, or that alcohol is secondary to some other initiating event. Hepatitis C virus (HCV) infection has been a strong candidate for this role. A recent study provides mechanistic details for this pathway and identifies FOXO3 (forkhead box transcription factor) as potential target for therapeutic intervention in alcoholic liver disease.
To test whether FOXO3 is protective for alcoholic liver injury, researchers fed alcohol to FOXO3(-/-) mice. After 3 weeks, one third of these mice developed severe hepatic steatosis, neutrophilic infiltration, and >10-fold alanine aminotransferase (ALT) elevations. In cell culture, either alcohol or HCV infection alone increased FOXO3 transcriptional activity and expression of target genes, but the combination of HCV and alcohol together caused loss of nuclear FOXO3 and decreased its transcriptional activity.
This was accompanied by increased phosphorylation of FOXO3. Mice expressing HCV structural proteins on a background of reduced expression of superoxide dismutase 2 (SOD2; Sod2(+/-)) also had increased liver sensitivity to alcohol, with elevated ALT, steatosis, and lobular inflammation. Elevated ALT was associated with an alcohol-induced decrease in SOD2 and redistribution of FOXO3 to the cytosol.
These results demonstrate that FOXO3 functions as a protective factor preventing alcoholic liver injury. The combination of HCV and alcohol, but not either condition alone, inactivates FOXO3, causing a decrease in expression of its target genes and an increase in liver injury. Modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcohol-induced liver injury.