Abstract
Alcohol use disorder remains a substantial social, health, and economic problem and problem drinking levels in women have been increasing in recent years. Understanding whether and how the underlying mechanisms that drive drinking vary by sex is critical and could provide novel, more targeted therapeutic treatments. Here, we examine recent results from our laboratories and others which we believe provide useful insights into similarities and differences in alcohol drinking patterns across the sexes. Findings for binge intake and aversion-resistant, compulsion-like alcohol drinking are considered, since both are likely significant contributors to alcohol problems in humans. We also describe studies regarding mechanisms that may underlie sex differences in maladaptive alcohol drinking, with some focus on the importance of nucleus accumbens (NAcb) core and shell regions, several receptor types (dopamine, orexin, AMPA-type glutamate), and possible contributions of sex hormones. Finally, we discuss how stressors such as early life stress and anxiety-like states may interact with sex differences to contribute to alcohol drinking. Together, these findings underscore the importance and critical relevance of studying female and male mechanisms for alcohol and co-morbid conditions to gain a true and clinically useful understanding of addiction and neuropsychiatric mechanisms and treatment.
Highlights
Despite considerable efforts across a number of decades, alcohol use disorder (AUD) continues to be a substantial health problem, with significant economic, social, medical, and legal costs [1,2,3,4,5,6]
Despite this relative lack of estrous cycle effects in alcohol drinking, there is physiological evidence suggesting that excitation of ventral tegmental area (VTA) dopamine neurons by alcohol is greatest in diestrus, when circulating estradiol levels are high [103]
We found that binge alcohol drinking (15%) on quinine-free sessions was not affected by selective chemogenetic inhibition of D1-receptor expressing “direct” pathway neurons (D1-neurons) or D2-receptor expressing “indirect” pathway neurons (D2-neurons)
Summary
Despite considerable efforts across a number of decades, alcohol use disorder (AUD) continues to be a substantial health problem, with significant economic, social, medical, and legal costs [1,2,3,4,5,6]. One goal is to identify key mechanisms that drive these pathological forms of alcohol consumption, since these may provide novel and translationally useful therapies to reduce the burden of alcohol-related costs This effort is considered especially critical since, at present, there are few pharmacotherapeutic options approved for AUD treatment [17]. There are multiple ways to conceptualize what compulsion reflects, from a stronger form of habit to a goal-directed process of overcoming conflict (which likely recruits habit as well as other circuits) (reviewed in [27,29]) Another critical consideration is the timing of the adverse consequence relative to intake, where negative outcomes often occur in the future for humans (e.g., loss of job, legal problems), while rodent models involve acute punishment or adversity. We find that female rodents have a heightened propensity for binge and compulsion-like behaviors, which is associated with sex-specific mechanisms in the nucleus accumbens (NAcb)
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