Summary: A new study reveals a history of binge drinking leads to more instances of drinking under stress and when anxious in males, but not in females.
Source: Veterans Affairs Research Communications.
Researchers with the Veterans Affairs Portland Health Care System and Oregon Health & Sciences University found that a history of binge drinking made male and female mice react differently to traumatic stress. The research may help scientists understand why men and women seem to handle both alcohol and stress differently.
The results were published in the September 2018 issue of the journal Alcohol.
A history of binge drinking is a strong predictor of alcohol dependence, and alcohol use disorder is often characterized by repeated episodes of binge drinking. Excessive drinking is the fourth leading preventable cause of death in the United States, and accounts for nearly 6 percent of deaths globally.
Stress may shift alcohol use from recreational to excessive, according to the researchers.
Posttraumatic stress disorder in particular has been linked with the development of alcohol use disorders. Of people with PTSD, 28 percent of women and 52 percent of men also have an alcohol use disorder. The rate of PTSD and alcohol use disorder together is even higher in the VA system, with reports of almost 70 percent in hospitalized veterans. The relationship between the two conditions goes both ways: PTSD symptoms appear to promote excessive drinking, and alcohol abuse worsens PTSD symptoms.
Past research has shown that abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis–interconnected biological systems that control how the body reacts to stress–are present in both PTSD and alcohol use disorder. Differences between the sexes have also been seen in how the HPA axis responds to stress.
So how do these biological differences between the sexes affect the complex relationship between alcohol use and PTSD?
To answer this question, the researchers looked to a mouse study.
They simulated binge drinking in mice by providing alcohol as the only source of hydration for the rodents. A group of male and female mice had seven intermittent binge drinking sessions, followed by a month of abstinence from access to alcohol. Another group of male and female mice drank water as a control.
The researchers then intermittently exposed the mice to dirty rat bedding to cause stress. Previous research has shown that the odor of predators can produce behavioral and physiological responses in rodents similar to those seen following traumatic stress in humans. An earlier phase of the study showed that the dirty rat bedding increased anxiety-related behavior and increased the levels of corticosterone–a stress hormone–in both male and female mice.
Lead author Dr. Deborah Finn, a research pharmacologist at the VA Portland Health Care System and professor in the department of behavioral neuroscience at OHSU, explains that her team used a device called the “elevated plus maze” to measure anxiety-related behavior in the mice.
“We measure the amount of time the mouse spends in the open and closed arms in the apparatus, and some other behaviors, during a five-minute test. A mouse that exhibits more anxiety-related behavior will spend more time in the closed, protected arms, whereas a mouse that exhibits less anxiety-related behavior will spend more time in the open arms.”
Before and after the mice were exposed to the dirty rat bedding, they were offered two bottles to drink from, one with alcohol and one with water. Each bottle was equipped with a “lickometer,” a device that recorded both the amount and frequency of drinking.
Male mice that previously had drunk water increased their alcohol licks by 24 percent after four stress periods over 22 days, compared with their baseline drinking prior to the beginning of the stress period. For male mice in the binge drinking group, ethanol licks increased by 65 percent. Drinking behavior after stress–how often the mice drank and how much they drank each time they went to the bottle–increased across time for the male binge group but not the control group.
In the female mice, no difference appeared between the binge-drinking group and the water group. Stress caused female mice to drink more alcohol, but the binge group did not increase their intake more than the control group, as was seen in the males. The female binge mice increased their alcohol licks by 5 percent, while the control group increased by 6 percent.
However, there were two clear subgroups in the females. One group of female mice increased their drinking much more than the group average, suggesting they were more sensitive to stress. For female mice in the stress-sensitive subgroup, binge females increased their drinking by 87 percent and control females increased their drinking by 214 percent, compared to the pre-stress baseline drinking levels. This result suggested to the researchers that this group had a more dramatic response to stress, when compared to the responses in males, but prior binge drinking did not exacerbate the response to stress as in the males.
The researchers found neurochemical and physiological differences between males and females, in addition to the changes in alcohol drinking behavior. When testing blood plasma, they found that predator stress exposure significantly increased corticosterone levels in mice that were consuming alcohol, with higher levels in females than in males. This finding is consistent with evidence for sex differences in HPA axis responsivity to stress.
However, the stress-induced increase in corticosterone levels was lower than that observed in the mice that had never consumed alcohol, especially in the male mice. This result suggested to the researchers that a history of alcohol drinking might dampen the stress response to predator odor, particularly in male mice.
The researchers also used a test called a Western blot to measure protein levels in the brain tissue of the mice. They focused on the prefrontal cortex and hippocampus, two brain regions that are important in the stress response. Two proteins involved in regulating the stress response, corticotropin releasing factor receptor 1 (CRF-R1) and glucocorticoid receptor (GR), were significantly increased by traumatic stress exposure and a history of alcohol drinking in the prefrontal cortex and hippocampus of female mice. Similar increases were not observed in the male mice. The clear sex difference in CRF-R1 and GR levels suggested that the HPA axis may respond differently in males and females to repeated traumatic stress and the long-term alcohol drinking.
While the research was conducted using mice, it could have implications for how humans react to both excessive drinking and traumatic stress.
Ample evidence from past research shows that men and women are affected differently both by stress and by alcohol. Lifetime prevalence of PTSD is reported to be twice as high in women as in men, whereas prevalence of alcohol use disorder with PTSD is higher in males than in females.
Men and women also tolerate alcohol differently, past studies show. In general, men seem to have a higher tolerance for alcohol than women. Past research suggests that there may be more complex chemistry involved than just body weight. For example, men may metabolize alcohol faster than women because their bodies produce more of an enzyme that breaks down alcohol in the liver. Women also develop alcohol-related problems such heart disease, liver damage, and brain damage after fewer years of heavy drinking, compared with men.
The researchers plan to use their model to look for biological and molecular mechanisms that could confer sensitivity or resilience to binge drinking and traumatic stress exposure. They emphasize that traumatic stress and binge drinking together have a greater effect than either on its own, and that men and women may need to be treated differently for these conditions. The lab research could eventually help lay the groundwork for new treatment strategies for veterans and others with both PTSD and alcohol use disorders.
Funding: Funding provided by Department of Veterans Affairs, Pacific University School of Pharmacy.
Source: Veterans Affairs Research Communications
Publisher: Organized by NeuroscienceNews.com.
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Original Research: Abstract for “Sex differences in the synergistic effect of prior binge drinking and traumatic stress on subsequent ethanol intake and neurochemical responses in adult C57BL/6J mice” by Deborah A. Finn, Melinda L. Helms, Michelle A. Nipper, Allison Cohen, Jeremiah P. Jensen, and Leslie L. Devaud in Alcohol. Published September 2018.
Sex differences in the synergistic effect of prior binge drinking and traumatic stress on subsequent ethanol intake and neurochemical responses in adult C57BL/6J mice
Alcohol-use disorders (AUDs) are characterized by repeated episodes of binge drinking. Based on reports that exposure to predator odor stress (PS) consistently increases ethanol intake, the present studies examined whether prior binge drinking differentially altered responsivity to PS and subsequent ethanol intake in male and female mice, when compared to mice without prior binge exposure. Initial studies in naïve male and female C57BL/6J mice confirmed that 30-min exposure to dirty rat bedding significantly increased plasma corticosterone (CORT) levels and anxiety-related behavior, justifying the use of dirty rat bedding as PS in the subsequent drinking studies. Next, separate groups of male and female C57BL/6J mice received seven binge ethanol sessions (binge) or drank water (controls), followed by a 1-month period of abstinence. Then, 2-bottle choice ethanol intake (10% or 10E vs. water, 23 h/day) was measured in lickometer chambers for 4 weeks. After baseline intake stabilized, exposure to intermittent PS (2×/week × 2 weeks) significantly enhanced ethanol intake after the 2nd PS in male, but not female, binge mice vs. baseline and vs. the increase in controls. However, in a subgroup of females (with low baselines), PS produced a similar increase in 10E intake in control and binge mice vs. baseline. Analysis of lick behavior determined that the enhanced 10E intake in binge male mice and in the female low baseline subgroup was associated with a significant increase in 10E bout frequency and 10E licks throughout the circadian dark phase. Thus, PS significantly increased 10E intake and had a synergistic interaction with prior binge drinking in males, whereas PS produced a similar significant increase in 10E intake in the low baseline subgroup of binge and control females. Plasma CORT levels were increased significantly in both binge and control animals after PS. CORT levels at 24-h withdrawal from daily 10E intake were highest in the groups with elevated 10E licks (i.e., binge males and control females). At 24-h withdrawal, protein levels of GABAA receptor α1 subunit, corticotropin releasing factor receptor 1, and glucocorticoid receptor in prefrontal cortex (PFC) and hippocampus (HC) were differentially altered in the male and female mice vs. levels in separate groups of age-matched naïve mice, with more changes in HC than in PFC and in females than in males. Importantly, the sexually divergent changes in protein levels in PFC and HC add to evidence for sex differences in the neurochemical systems influenced by stress and binge drinking, and argue for sex-specific pharmacological strategies to treat AUD.