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Glucocorticoid Receptor‐Dependent Gene Expression in the Central Amygdala of Alcohol‐Dependent Animals
Author(s) -
McGinn Mary Adrienne,
Edwards Kim,
Edwards Scott
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.878.7
Subject(s) - glucocorticoid , glucocorticoid receptor , mifepristone , amygdala , alcohol use disorder , endocrinology , medicine , self administration , neuropeptide , alcohol dependence , receptor , psychology , alcohol , pharmacology , chemistry , biology , genetics , pregnancy , biochemistry
Alcohol Use Disorder (AUD) is a chronic, relapsing psychiatric disorder that is characterized by the development of motivational symptoms (e.g., escalation of alcohol intake) and the parallel emergence of negative emotional states (e.g., dysphoria, anxiety, pain). Consequently, the transition from recreational, limited alcohol consumption to uncontrolled, escalated intake is proposed to involve a transition from positive to negative reinforcement mechanisms. Our previous research indicates that alcohol dependence is associated with potentiated glucocorticoid signaling in brain regions that mediate stress and nociception, namely the central amygdala (CeA). Glucocorticoid receptor (GR) antagonism with mifepristone has demonstrated promising efficacy in reducing alcohol consumption in humans with AUD and rodent models of alcohol dependence. However, mifepristone's mechanism of action remains unclear. Given the role of GR as a transcription factor, we hypothesized that potentiated GR activity increases the expression of downstream neuropeptide system genes, and mifepristone normalizes these transcriptional effects. We tested our hypothesis in a well‐ established rodent model of AUD that utilizes chronic intermittent ethanol vapor exposure (CIEV). One day prior to the start of vapor exposure, animals were implanted with either placebo or 30d chronic release mifepristone pellets. After the 4‐week treatment regimen, we utilized a fluorescent bead‐based multiplex assay to determine brain region‐specific changes in mRNA levels of expected GR‐regulated genes. Results were analyzed via two‐way ANOVA, with alcohol vapor exposure (modeling alcohol dependence) and mifepristone treatment as factors. We found that within the CeA, alcohol dependence was associated with increased mRNA coding for the nociceptin peptide as well as its receptor, opioid receptor‐like 1 (Orl1), while mifepristone treatment significantly attenuated this effect. The nociceptin system is a part of the endogenous opioid class of signaling molecules, and previous research has demonstrated a role for nociceptin in both chronic pain and the manifestation of negative affect during alcohol withdrawal. Our findings suggest that the therapeutic benefits of mifepristone could be associated with a blunting of the nociceptin system in the central amygdala. Support or Funding Information Our research is supported by the following grants from the National Institute on Alcohol Abuse and Alcoholism: F31AA025812 (MAM) and R00AA020839 (SE). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .