Role of histaminergic regulation of astrocytes in alcohol use disorder

Alcohol use disorder (AUD) is a severe, yet not fully understood, mental health problem. It is associated with liver, pancreatic, and gastrointestinal diseases, thereby highly increasing the morbidity and mortality of these individuals. Currently, there is no effective and safe pharmacological therapy for AUD. Therefore, there is an urgent need to increase our knowledge about its neurophysiological etiology to develop new treatments specifically targeted at this health condition. Recent findings have shown an upregulation in the histaminergic system both in alcohol dependent individuals and in animals with high alcohol preference. The use of H3 histaminergic receptor antagonists has given promising therapeutic results in animal models of AUD. Interestingly, astrocytes, which are ubiquitously present in the brain, express the three main histamine receptors (H1, H2 and H3), and in the last few years, several studies have shown that astrocytes could play an important role in the development and maintenance of AUD. Accordingly, alterations in the density of astrocytes in brain areas such as the prefrontal cortex, ventral striatum, and hippocampus that are critical for AUD-related characteristics have been observed. These characteristics include addiction, impulsivity, motor function, and aggression. In this work, we review the current state of knowledge on the relationship between the histaminergic system and astrocytes in AUD and propose that histamine could increase alcohol tolerance by protecting astrocytes from ethanol-induced oxidative stress. This increased tolerance could lead to high levels of alcohol intake and therefore could be a key factor in the development of alcohol dependence.