Prenatal infection increases risk of alcohol misuse in adulthood

Exposure to infection and other immune stress in the womb increases the likelihood of alcohol misuse in adulthood, a risk that may be reduced through prenatal antioxidant treatment, a new Washington State University study shows.

The findings, published in the journal Psychopharmacology, provide insight into how early biological stress shapes addictive behaviors and identifies a potential approach for lowering the risk of alcohol use disorder - a problem with massive social and financial costs. 

People don't talk about alcohol use disorder as much as other drugs because alcohol is legal. But alcohol use disorder affects more people than all the other drugs. There really is the need to better understand the mechanisms by which this is happening so we can develop better interventions to reduce some of these societal costs."

Angela M. Henricks, assistant professor in the WSU Department of Psychology and corresponding author of the publication

Excessive drinking causes an estimated 178,000 deaths per year and has an annual cost of $249 billion in lost workplace productivity, health-care expenses and other factors, according to the U.S. Centers for Disease Control.

The research expands on current understanding of how prenatal factors such as infection, diet and stress influence lifelong health. While it's known that prenatal infection is associated with neuropsychiatric disorders linked with alcohol misuse, the exact mechanisms remain unknown. 

"What we don't understand is how that changes the brain to make someone more susceptible to mental illness or substance abuse disorder," Henricks said. "We know it's a risk factor, but we don't know how it works very well."

Henricks and her team examined how maternal immune activation - the body's response to infection, stress or inflammation – affects the desire to drink alcohol later in life. They also investigated whether treatment with the antioxidant N-acetylcysteine, or NAC, could block those effects.

Using a well-established animal model, pregnant rats were exposed to a synthetic substance that mimics a virus. Some received NAC before and after immune activation, while controls received saline.

Offspring exposed to prenatal immune stress showed increased motivation to self-administer alcohol in adulthood - if they had also been exposed to alcohol in adolescence. This supports a "two-hit" model of addiction risk, in which early immune stress interacts with later life experiences to raise the likelihood of a use disorder.

However, prenatal antioxidant treatment suppressed this response. That suggests that the presence of oxidative stress, which occurs when there is too much DNA-damaging oxidation in cells, may be important and indicates that NAC may offer a treatment to lower the risk of alcohol misuse in humans.

"This suggests that oxidative stress is significantly contributing to why prenatal infection might be a risk factor," Henricks said.

Notably, the effects were sex-specific. Male offspring were more sensitive to the impact of prenatal infection and showed the clearest response to antioxidant treatment, while females did not show the same increase in alcohol-seeking behavior.

That underscores the importance of considering biological sex in addiction research and prevention and may shed light on why males are more susceptible to neurodevelopmental and substance use disorders.

A team from Henricks' Brain Alcohol Research Lab were co-authors on the paper: PhD student Skylar E. Nicholson, who was the lead author, PhD student Kelly A. Hewitt, and Cara S. Brauen, who was an undergraduate research assistant during the project.

Henricks is doing further research to explore the effects of prenatal immune stress, including a similar study of cannabis use. She's also working to develop a better picture of how oxidative stress affects the brain.

"One thing we think oxidative stress is doing to the brain is impacting synaptic plasticity, which is essentially the ability of your neurons to make connections with one another," she said.