Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence
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.
Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels
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.
MicroRNA expression profile and functional analysis reveal that miR-382 is a critical novel gene of alcohol 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.
Hepatitis C and alcohol exacerbate liver injury by suppression of FOXO3
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.
Combined use of alcohol, cigarettes, and marijuana in early adolescence can lead to substance dependence in early adulthood
Alcohol, tobacco, and marijuana are the substances American adolescents use the most. A recent study led by researchers at the National Institute on Alcohol Abuse and Alcoholism examined how adolescents’ substance use patterns are associated with substance use disorders in young adulthood. Their findings, published in Drug and Alcohol Dependence in March 2014, show that adolescents who drink alcohol and also smoke cigarettes and marijuana are more likely to suffer from alcohol and other substance use disorders as young adults than adolescents who delay trying these substances.
The researchers used data from Waves I (1994–1995) and IV (2008) of the National Longitudinal Study of Adolescent Health (Add Health), the largest, most comprehensive survey of adolescents in the United States, to estimate the prevalence of various patterns of early adolescent use of alcohol, cigarettes, and marijuana, individually and in combination. They also examined the differences in these patterns based on age, gender, and race/ethnicity among users of all three substances. Then, they examined the effects of these patterns on subsequent young adult substance use behaviors and DSM-IV substance use disorders.
Researchers found that multiple substance use is highly prevalent among U.S. adolescents, with 34.1% reporting early use of alcohol and marijuana, or alcohol, marijuana and cigarettes. They also found that early use of multiple substances is associated with higher rates of substance use dependence in young adults. According to their analyses, about one-fourth of young adults ages 24 to 32 who had used alcohol, marijuana, and cigarettes before age 16 met the DSM-IV criteria for a substance use disorder. By contrast, only about 16% of young adults who had used these same substances after age 16 met the criteria for a substance use disorder.
The researchers also examined the associations between the use of multiple substances in early adolescence with a range of subsequent young adult substance use behaviors. They found that adolescents who used alcohol, cigarettes, and marijuana prior to age 16 were twice as likely to meet the criteria for marijuana dependence and three times as likely to be dependent on other illicit drugs.
The authors conclude that prevention programs should aim to encourage kids to delay use of all three problematic substances – alcohol, cigarettes, and marijuana – rather than targeting each substance separately.