Targeting Mood Disorders in Alcohol Withdrawal
Mood disorders such as anxiety and depression are strongly associated with alcohol use disorder and can be exacerbated during alcohol withdrawal. In fact, the increase in anxiety and depression associated with withdrawal contributes to the likelihood of relapse and return to alcohol abuse. Treatment of mood disorders in patients suffering from alcohol use disorder is difficult because most antidepressant drugs require weeks to months to be effective, and ethanol potentiates their side effects. Thus, a rapid, effective treatment for mood disorders, particularly during alcohol withdrawal, is sorely needed. Recent work had suggested that the anesthetic ketamine, given at low doses, could provide relief of symptoms in animal models of alcohol withdrawal-related depression. To better define the parameters for optimal therapy, Vanderbilt Basic Sciences investigator Danny Winder and his lab explored the effects of administration time on ketamine’s effects in mice undergoing ethanol withdrawal. They found that mice exposed to six weeks of ethanol consumption displayed symptoms of anxiety within the first week of forced abstinence, and then depression after two weeks of abstinence as assessed by standard tests. Administration of a single dose of ketamine at the initiation of abstinence reduced the symptoms of both anxiety and depression. However, administration of ketamine at 2 days or 6 days following the start of abstinence had no effect. To better understand ketamine’s mechanism of action, the investigators measured the electrical activity of the bed nucleus of the stria terminalis (BNST) in brain slices from mice experiencing alcohol withdrawal with or without ketamine therapy. The BNST is a region of the brain known to be involved in both ethanol use disorder and mood-related behaviors. The data revealed that following 2 to 3 weeks of ethanol withdrawal, BNST neurons exhibited a reduction in their ability to develop both short-term and long-term potentiation, indicating a loss of plasticity. These changes were blocked by administration of ketamine at the start of withdrawal, but not 6 days later. Together the results confirm the potential of ketamine to be an effective treatment for mood disorders related to alcohol withdrawal; however, the window for administration of the drug appears to be very narrow. The data also suggest that ketamine may work by preventing a withdrawal-mediated loss of plasticity in the BNST. The researchers point out that this effect may be associated with the GluN2B subunit of the N-methyl-D-aspartate receptor, which exhibits altered expression during ethanol consumption and withdrawal. Future research will explore this potentially key relationship. The work is published in the journal Neuropsychopharmacology [O. Vranjkovic, et al., (2017) Neuropsychopharmacology, published online May 24, DOI: 10.1038/s41386-018-0102-0].