期刊
BIOLOGICAL PSYCHIATRY
卷 70, 期 6, 页码 575-582出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2011.03.019
关键词
Addiction; AKT; alcohol; GSK-3; nucleus accumbens; PI3K
资金
- National Institutes of Health-National Institute on Alcohol Abuse and Alcoholism [P50 AA017072]
- State of California for Medical Research on Alcohol and Substance Abuse through the University of California, San Francisco
Background: Neuroadaptations within the nucleus accumbens (NAc) have been implicated in molecular mechanisms underlying the development and/or maintenance of alcohol abuse disorders. We recently reported that the activation of mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in the NAc of rodents, after exposure to alcohol, contributes to alcohol drinking behaviors. The kinase AKT is a main upstream activator of the mTORC1 pathway. We therefore hypothesized that the activation of AKT in the NAc in response to alcohol exposure plays an important role in mechanisms that underlie excessive alcohol consumption. Methods: Western blot analysis was used to assess the phosphorylation levels of enzymes. Acute exposure of mice to alcohol was achieved by the administration of 2 g/kg alcohol intraperitoneally (IP). Two-bottle choice and operant self-administration procedures were used to assess drinking behaviors in rats. Results: We found that acute systemic administration of alcohol and recurring cycles of excessive voluntary consumption of alcohol and withdrawal result in the activation of AKT signaling in the NAc of rodents. We show that inhibition of AKT or its upstream activator, phosphatidylinositol-3-kinase (PI3K), within the NAc of rats attenuates binge drinking as well as alcohol but not sucrose operant self-administration. Conclusions: Our results suggest that the activation of the AKT pathway in the NAc in response to alcohol exposure is an important contributor to the molecular mechanisms underlying alcohol-drinking behaviors. AKT signaling pathway inhibitors are therefore potential candidates for drug development for the treatment of alcohol use and abuse disorders.
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