Brain Serotonin Deficiency Increases Susceptibility to Stress‐Induced Increases in Binge Drinking in Females, but not Males

Abstract

Approximately 30 million Americans currently suffer from alcohol use disorders (AUDs), which cost the US economy over $249 billion annually. Men are more likely than women to have an AUD, but rates of AUDs in women are rising rapidly, and women tend to experience more negative health consequences from excessive alcohol consumption than men. The causes of gender disparities in AUDs and alcohol responses remain unknown, but stress has been associated with the development of AUDs, particularly in women, and genetic factors are thought to increase AUD risk. Although the specific genetic factors that confer AUD risk have not been conclusively established, dysfunction of the brain serotonin (5‐HT) system has been hypothesized to play a role. Based on our published work demonstrating that brain 5‐HT deficiency increases susceptibility to stress, we hypothesized that low brain 5‐HT would predispose animals to excessive alcohol consumption following stress. Our unpublished findings demonstrate that chronic restraint stress increases binge‐like alcohol consumption in the drinking in the dark paradigm in 5‐HT‐deficient females but not in WT females or in males of either genotype. In contrast, in the absence of stress, low 5‐HT increased binge‐like drinking in males only. The precise molecular mechanisms underlying this enhanced susceptibility of 5‐HT‐deficient females to stress‐induced binge drinking have not been conclusively established, but RNA sequencing studies followed by gene ontology enrichment analysis reveals that chronic stress leads to dysregulation of several gene sets involved in serotonin signaling and alcoholism in 5‐HT‐deficient females, but not in WT females. These data provide new insight into the mechanisms through which low 5‐HT impacts stress‐sensitive behaviors in a sex‐dependent manner.