Alcohol use disorder: Blocking hippocampal STAT3 during withdrawal can alleviate depression

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A discovery from researchers at the University of Illinois Chicago may lead to new treatments for individuals who suffer from alcohol use disorder and depression.

The study, “Transcriptomics identifies STAT3 as a key regulator of hippocampal gene expression and anhedonia during withdrawal from chronic alcohol exposure,” is published in the journal Translational Psychiatry by researchers at UIC’s Center for Alcohol Research in Epigenetics.

During withdrawal from long-term alcohol use, people often suffer from depression, which may cause them to start drinking again as a way to self-medicate. If we can treat that aspect, we hope we can prevent people from relapsing,” said Amy Lasek, UIC associate professor of psychiatry and anatomy and cell biology at the College of Medicine, and an author of the study.

Withdrawal from chronic alcohol drinking can often result in depression. For this study, researchers removed postmortem hippocampus samples of rats in alcohol withdrawal. The hippocampus is a brain region that plays a role in depression and cognitive function.

Researchers conducted RNA sequencing of all the RNA transcripts in the hippocampus and looked for those that were changed during withdrawal from alcohol.

One of the RNA transcripts that was changed makes a protein called STAT3.

STAT3 is a transcription factor that controls the expression of many different genes, including immune response genes. Notably, several known STAT3-regulated genes were also increased in the hippocampus during withdrawal from alcohol, indicating that STAT3 might be a “master regulator” of several genes in the hippocampus during withdrawal.

The rats were treated during withdrawal with a compound that blocks STAT3 activity. The rats’ withdrawal-induced anhedonia, or inability to feel pleasure, was alleviated.

Additionally, researchers looked at the same genes in human postmortem hippocampus samples of individuals who had a medical diagnosis of alcohol use disorder, alcoholism. They found that STAT3 and its target genes were elevated in the postmortem hippocampus of human subjects who died without alcohol in their systems – in withdrawal or abstinent from alcohol – when compared to samples from control subjects who did not have alcohol use disorder.

These results were strikingly similar to the results found in the rat study.

“The human and rat studies are similar, which might mean that our rat results can potentially be applied to humans. We haven’t done any treatments of people with alcohol use disorder, but we can see from the rat data that if we block STAT3 during withdrawal we can alleviate depression,” Lasek said.

Some genes regulated by STAT3 are involved in the innate immune response in the brain. There is a known connection between hyperactive immune response and major depressive disorder, Lasek said.

“We know that chronic alcohol use can induce an immune response in the brain. By inhibiting STAT3, we think that we are dampening that hyperactive immune response by blocking the ability of STAT3 to increase the expression of these immune-response genes during withdrawal, Lasek said.

Lasek said inflammation in the brain is currently a hot research topic and further research may determine if dampening the brain’s inflammatory response could treat psychiatric disorders.

Antidepressants currently available are not effective in reducing alcohol drinking. And other drugs available to treat alcohol use disorder are not universally effective. Further study for a better understanding of how STAT3 works could hopefully lead to more effective interventions for alcohol use disorder and related depression, Lasek said.

In addition to Lasek, the paper’s authors are Hu Chen, Kana Hamada, Eleonora Gatta, Ying Chen, Huaibo Zhang, Jenny Drnevich, Harish Krishnan, Mark Maienschein-Cline, Dennis Grayson, and Subhash Pandey, all of UIC, and Wei-Yang Chen of the University of Washington, Seattle.


What is Alcohol Withdrawal Syndrome?

Alcohol withdrawal syndrome is a set of symptoms that occur when someone who is physically dependent upon alcohol suddenly stops drinking or drastically reduces their alcohol intake.

Alcohol withdrawal is thought to arise as a function of various changes in brain activity caused by prolonged and excessive alcohol use. Though the neurochemical details of alcohol withdrawal syndrome are somewhat complicated, its associated symptoms reflect a compensation for previous disruptions in both excitatory and inhibitory neurotransmitter activity—the balance between the two having been upended to begin with as a result of prolonged alcohol use.5

“Alcohol withdrawal is thought to arise as a function of various changes in brain activity caused by prolonged and excessive alcohol use.”

The effects alcohol has on the body are complex, but two particular neurochemicals contribute to both short-term effects of drinking as well as the development of alcohol withdrawal syndrome when someone stops drinking: the brain’s main inhibitory chemical, gamma aminobutyric acid (GABA) and the brain’s main excitatory chemical, glutamate.6

When a person drinks alcohol it changes the functioning of GABA receptors as well as certain glutamate receptors, resulting in a slowdown of brain functioning that a person typically experiences as decreased anxiety and sedation.

The brain reacts by decreasing the amount of GABA being released and increasing glutamate signaling to compensate for how alcohol alters these levels.6 This adaptation functions as long as you continue to drink alcohol—this is known as “tolerance.”

Alcohol Withdrawal Timeline & Stages

What happens to your body when you give up alcohol may hinge on a variety of factors. Depending on the level of physiological alcohol dependence, the severity of acute alcohol withdrawal will vary for different individuals.3,8

The American Academy of Family Physicians outlines 3 potential stages that a person in withdrawal may experience. These include:9

  • Stage 1 (mild): symptoms may include headache, insomnia, anxiety, hand tremor, gastrointestinal disturbances, and heart palpitations.
  • Stage 2 (moderate): symptoms my include Stage 1 mild symptoms in addition to increased blood pressure or heart rate, confusion, mild hyperthermia, and rapid abnormal breathing.
  • Stage 3 (severe): symptoms include Stage 2 moderate symptoms in addition visual or auditory hallucinations, seizures, disorientation, and impaired attention.
alcohol abuse withdrawal

Without treatment by a healthcare professional, some people can progress from Stage 2 to Stage 3 rapidly.8

While a precise timeline for alcohol withdrawal will vary from person to person based on several factors (average quantity and duration of heavy drinking behavior, the concurrent presence of physical and mental health issues, etc.), a general symptom timeline for alcohol detox may look something like:7,9

  • 6-12 hours after the last drinkthe relatively mild symptoms of early withdrawal may begin to be felt, including some headache, mild anxiety, insomnia, small tremors, and stomach upset.
  • By 24 hours, some people may have begun to experience visual, auditory, or tactile hallucinations.
  • Within 24-72 hours, various symptoms may have peaked and begun to level off or resolve (though some more protracted symptoms may stick around for weeks or longer). Seizure risks may be highest from 24-48 hours after the last drink, requiring close monitoring and seizure prophylaxis. Withdrawal delirium (i.e., DTs) may appear from 48-72 hours after drinking has stopped.

More rarely, some people experience more persistent withdrawal related symptoms—such as sleep disturbances, fatigue, and changes in mood—that last for months.9 It is important to note, however, that most people recover fully with proper medical detox and withdrawal management services.11

Sources:

  1. Centers for Disease Control and Prevention. (2020). Dietary Guidelines.
  2. Centers for Disease Control and Prevention. (2018). Alcohol and substance misuse.
  3. Substance Abuse and Mental Health Services Administration. (2020). Key substance use and mental health indicators in the United States: Results from the 2019 National Survey on Drug Use and Health. Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration.
  4. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.
  5. American Family Physician. (2004). Alcohol Withdrawal Syndrome.
  6. Bayard, M., McIntyre, J., Hill, K.R., & Woodside, J. Jr. (2004). Alcohol withdrawal syndromeAmerican Family Physician, 69(6), 1443-1450.
  7. Gortney, J.S., Raub, J.N., Patel, P., Kokoska, L., Hannawa, M., & Argyris, A. (2016). Alcohol withdrawal syndrome in medical patientsCleveland Clinic Journal of Medicine, 83(1), 67-79.
  8. Center for Substance Abuse Treatment. (2006). Detoxification and substance abuse treatment. Treatment Improvement Protocol (TIP) Series 45, DHHS Publication No. (SMA) 06-4131. Rockville, MD: Substance Abuse and Mental Health Services Administration.
  9. Muncie Jr., H. L., Yasinian, Y., & Oge, L. K. (2013). Outpatient management of alcohol withdrawal syndrome.American Family Physician, 88(9), 589-595.
  10. National Library of Medicine. (2020).Alcohol withdrawal.
  11. National Institute on Drug Abuse.(2020). Principles of drug addiction treatment: A research-based guide (Third edition).
  12. National Health Service. (2018). Overview: Alcohol-related liver disease
  13. National Institute of Alcohol Abuse and Alcoholism. The neurotoxicity of alcohol.

Original Research: Open access.
Transcriptomics identifies STAT3 as a key regulator of hippocampal gene expression and anhedonia during withdrawal from chronic alcohol exposure” by Wei-Yang Chen, Hu Chen, Kana Hamada, Eleonora Gatta, Ying Chen, Huaibo Zhang, Jenny Drnevich, Harish R. Krishnan, Mark Maienschein-Cline, Dennis R. Grayson, Subhash C. Pandey & Amy W. Lasek. Translational Psychiatry

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