A study by researchers at Vanderbilt University Medical Center is offering a glimmer of hope to alcoholics who find it hard to remain sober because their abstinence is hounded by stubborn, difficult-to-treat depression.
Using an anesthetic drug that also has antidepressant properties, and another drug that raises levels of a mood-enhancing natural chemical in the brain, the researchers found that they could alleviate depressive-like symptoms in a mouse model of alcoholism.
The findings, published online this month in the journal Neuropsychopharmacology, could set the stage for development of novel treatments for mood and anxiety disorders that are induced by withdrawal from alcohol.
Depression is highly associated with alcohol abuse disorders. Yet before these findings can be applied to humans, “much work remains to be done,” said senior author Danny Winder, Ph.D., professor of Molecular Physiology and Biophysics and of Psychiatry.
Clinical studies in which both conditions have been treated at the same time are “woefully lacking,” he and his colleagues wrote. In addition, commonly used antidepressants called selective serotonin reuptake inhibitors (SSRI) are not very effective in this population.
The Vanderbilt researchers validated a previously established mouse model in which the animals exhibit depression-like behavior following withdrawal of alcohol.
They then tested ketamine, an anesthetic drug that blocks the NMDA receptor in the brain and which has been shown to have rapid and long-lasting antidepressant effects in humans. When the mice were given ketamine, the depressive symptoms were reversed.
The researchers also tested the effect of raising brain levels of an endocannabinoid called 2-AG by blocking the enzyme monoacylglycerol (MAG) lipase. Endocannabinoids are naturally produced chemical messengers that have been implicated in depression and anxiety-like behavior.
A previous Vanderbilt study found that raising 2-AG levels with an MAG lipase inhibitor reduced stress-induced anxiety-like behaviors in mice. In the current study, treatment with a MAG lipase inhibitor had a similar effect to ketamine in reversing depressive symptoms after alcohol withdrawal.
“We are excited to pursue the role of the endocannabinoid system further,” Winder said. But clinical use of ligands (compounds) that bind endogenous cannabinoid receptors is still in its infancy, he said.
Winder’s co-authors included first author Katherine Holleran, a graduate student in the Vanderbilt Neuroscience Graduate Program, and Sachin Patel, M.D., Ph.D., associate professor of Psychiatry and of Molecular Physiology and Biophysics.
Funding: The study was supported by National Institutes of Health grants AA021623, AA019455 and MH103950, and by the Brain & Behavior Research Foundation, formerly the National Alliance for Research on Schizophrenia and Depression (NARSAD).
Source: Craig Boerner – Vanderbilt University Medical Center
Image Source: The image is in the public domain
Original Research: Abstract for “Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive Behavior during Forced Abstinence from Alcohol Drinking” by Katherine M Holleran, Hadley H Wilson, Tracy L Fetterly, Rebecca J Bluett, Samuel W Centanni, Rachel A Gilfarb, Lauren ER Rocco, Sachin Patel and Danny G Winder in Neuropsychopharmacology. Published online January 11 2016 doi:10.1038/npp.2016.3
Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive Behavior during Forced Abstinence from Alcohol Drinking
While alcoholism and depression are highly comorbid, treatment options that take this into account are lacking, and mouse models of alcohol (ethanol, EtOH) intake-induced depressive behavior have not been well established. Recent studies utilizing contingent EtOH administration through prolonged two-bottle choice access have demonstrated depression-like behavior following EtOH abstinence in singly-housed female C57BL/6J mice. In the present study, we found that depression-like behavior in the forced swim test (FST) is revealed only after a protracted (2 weeks), but not acute (24 h), abstinence period. No effect on anxiety-like behavior in the EPM was observed. Further, we found that once established, the affective disturbance is long-lasting, as we observed significantly enhanced latencies to approach food even 35 days after ethanol withdrawal in the novelty-suppressed feeding test (NSFT). We were able to reverse affective disturbances measured in the NSFT following EtOH abstinence utilizing the N-methyl D-aspartate receptor (NMDAR) antagonist and antidepressant ketamine, but not memantine, another NMDAR antagonist. Pretreatment with the monoacylglycerol (MAG) lipase inhibitor JZL-184 also reduced affective disturbances in the NSFT in ethanol withdrawn mice, and this effect was prevented by co-administration of the CB1 inverse agonist rimonabant. Endocannabinoid levels were decreased within the BLA during abstinence compared to during drinking. Finally, we demonstrate that the depressive behaviors observed do not require a sucrose fade, and that this drinking paradigm may favor the development of habit-like EtOH consumption. These data could set the stage for developing novel treatment approaches for alcohol-withdrawal-induced mood and anxiety disorders.
“Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive Behavior during Forced Abstinence from Alcohol Drinking” by Katherine M Holleran, Hadley H Wilson, Tracy L Fetterly, Rebecca J Bluett, Samuel W Centanni, Rachel A Gilfarb, Lauren ER Rocco, Sachin Patel and Danny G Winder in Neuropsychopharmacology. Published online January 11 2016 doi:10.1038/npp.2016.3