Sex Differences in the Neurobiology of Alcohol Use Disorder

Abstract

Sex differences may play a critical role in modulating how chronic or heavy alcohol use impacts the brain to cause the development of alcohol use disorder (AUD). AUD is a multifaceted and complex disorder driven by changes in key neurobiological structures that regulate executive function, memory, and stress. A three-stage framework of addiction (binge/intoxication; withdrawal/negative affect; preoccupation/anticipation) has been useful for conceptualizing the complexities of AUD and other addictions. Initially, alcohol drinking causes short-term effects that involve signaling mediated by several neurotransmitter systems such as dopamine, corticotropin releasing factor, and glutamate. With continued intoxication, alcohol leads to dysfunctional behaviors that are thought to be due in part to alterations of these and other neurotransmitter systems, along with alterations in neural pathways connecting prefrontal and limbic structures. Using the three-stage framework, this review highlights examples of research examining sex differences in drinking and differential modulation of neural systems contributing to the development of AUD. New insights addressing the role of sex differences in AUD are advancing the field forward by uncovering the complex interactions that mediate vulnerability.

Keywords: adolescence; alcohol; alcohol use disorder; animal models; brain; sex differences; stress.

Figure 1

Sex differences in the effects of alcohol on the interacting brain systems associated with the three stages of addiction. Note: BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; CRF-R1, corticotropin-releasing factor receptor 1; GABA_A receptors, gamma-aminobutyric acid type A receptors; GR, glucocorticoid receptors; mPFC, medial prefrontal cortex; mRNA, messenger RNA; NAc, nucleus accumbens; PFC, prefrontal cortex; VTA, ventral tegmental area. Created with BioRender.