Newly published research is helping to make sense of data indicating that males and females not only consume alcohol differently, but respond differently when, if they are heavy users, they are forced abruptly to abstain from drinking. The results are relevant to efforts to develop new treatments for alcohol and other substance-use disorders.

A team led by 2018 BBRF Young Investigator Nicole Crowley, Ph.D., of Pennsylvania State University, studied “forced abstinence” in mice that modeled alcohol-use disorder (AUD) in people. Their aim was to learn about how an involuntary cessation of habitual alcohol consumption affects interconnected networks of neural circuits that can generate depression and anxiety.

It has been proposed that symptoms and underlying neural pathology overlap in alcohol-use disorder and depression and anxiety disorders. Forced abstinence is known to generate depression and anxiety in some individuals, but patterns differ in males and females, both in mice and humans.

Dr. Crowley and colleagues were intrigued by experiments indicating that treatment with the experimental rapid-acting antidepressant ketamine can reduce binge drinking and depressive-like behavior in rodents. This suggests that some of the potentially overlapping neural circuitry in alcohol-use disorder (AUD) and major depression involves a subset of inhibitory neurons in the brain called somatostatin-expressing neurons (SSTs).

SST neurons, like other inhibitory neurons, reduce communication between cells in the brain. Learning more about the role of SST neurons in parts of the brain involved in regulating emotions and adapting to stresses—such as forced abstinence in heavy alcohol users—was a focus of the research newly reported by Dr. Crowley’s team, in Frontiers in Behavioral Neuroscience. The study’s first author was Nigel Dao.

The researchers randomly assigned male and female mice to two groups: one group had access only to tap water; the other to both tap water and alcohol. Mice in this second group were free to drink alcohol if they chose to do so. Concentration of the alcohol was gradually increased from 3% in the initial days of the trial to 10% by the end of the 42-day trial period. For those mice consuming alcohol, abstinence was forced after the 42nd day—only tap water was offered to all mice at this point. The trial continued for 21 additional days.

As had been observed in past studies, both male and female mice showed a preference, generally, for alcohol over water, when available; and females drank more than males. Both sexes, also, showed an increase in various depressive-like behaviors when alcohol was withdrawn. Both sexes had symptoms corresponding with anhedonia, a lack of interest in seeking pleasure.

But there were differences in the responses of the sexes to certain tests given to mice to gauge their response to stressors like forced abstinence. This led the team to hypothesize that females transition to an abstinence-induced depressive state more rapidly than males. Future research, the team suggested, should more closely study the way men and women progress over time through different mood states during alcohol withdrawal.

Behavioral adaptation to stress “may be more nuanced in female mice,” the researchers reported. The team’s experiments suggested that forced abstinence induced sex-specific alterations in the prefrontal cortex (PFC)—dampening activation of excitatory neurons in the PFC in female mice (but not in males). In response to stress, abnormally low activation of part of the PFC called the medial prefrontal cortex, as well as changes in the amygdala, have been observed in people with major depression and alcoholism, the team noted.

SST neurons may confer resilience to stressors like forced abstinence—a concept that could have future therapeutic implications. Broadly, the research suggests that the remodeling of components of the brain’s stress-response network could be an aim of future therapeutic strategies for alcohol-use disorder and perhaps other substance use disorders.