Role of microglia in stress-induced alcohol intake in female and male mice.

Rates of alcohol use disorder (AUD) have escalated in recent years, with a particular increase among women. Women are more susceptible to stress-induced alcohol drinking, and preclinical data suggest that stress can increase alcohol intake in female rodents; however, a comprehensive understanding of sex-specific neurobiological substrates underlying this phenomenon is still emerging. Microglia, the resident macrophages of the brain, are essential for reshaping neuronal processes, and microglial activity contributes to overall neuronal plasticity. We investigated microglial dynamics and morphology in limbic brain structures of male and female mice following exposure to stress, alcohol or both challenges. In a modified paradigm of intermittent binge drinking (repeated "drinking in the dark"), we determined that female, but not male, mice increased their alcohol consumption after exposure to a physical stressor and re-exposure trials in the stress-paired context. Ethanol (EtOH) drinking and stress altered a number of microglial parameters, including overall number, in subregions of the amygdala and hippocampus, with effects that were somewhat more pronounced in female mice. We used the CSF1R antagonist PLX3397 to deplete microglia in female mice to determine whether microglia contribute to stress-induced escalation of EtOH intake. We observed that microglial depletion attenuated stress-induced alcohol intake with no effect in the unstressed group. These findings suggest that microglial activity can contribute to alcohol intake under stressful conditions, and highlight the importance of evaluating sex-specific mechanisms that could result in tailored interventions for AUD in women.

Sex differences in stress-induced alcohol intake: a review of preclinical studies focused on amygdala and inflammatory pathways.

Clinical studies suggest that women are more likely than men to relapse to alcohol drinking in response to stress; however, the mechanisms underlying this sex difference are not well understood. A number of preclinical behavioral models have been used to study stress-induced alcohol intake. Here, we review paradigms used to study effects of stress on alcohol intake in rodents, focusing on findings relevant to sex differences. To date, studies of sex differences in stress-induced alcohol drinking have been somewhat limited; however, there is evidence that amygdala-centered circuits contribute to effects of stress on alcohol seeking. In addition, we present an overview of inflammatory pathways leading to microglial activation that may contribute to alcohol-dependent behaviors. We propose that sex differences in neuronal function and inflammatory signaling in circuits centered on the amygdala are involved in sex-dependent effects on stress-induced alcohol seeking and suggest that this is an important area for future studies.