Noradrenergic mechanisms and circuitry of hyperkatifeia in alcohol use disorder.

Hyperkatifeia, the manifestation of emotional distress or pain, is a conceptual framework gaining traction throughout the alcohol and other substance use fields as an important driver of addiction. It is well known that previous or current negative life experiences can serve as powerful motivators for excessive alcohol consumption and precipitate the development of an alcohol use disorder (AUD). A major hallmark of later stages of AUD is the emergence of hyperkatifeia during withdrawal, which can persist well into protracted abstinence to drive relapse. Given these complex interactions, understanding the specific neuroadaptations that lie at the intersection of hyperkatifeia and AUD can inform ongoing therapeutic development. Of particular interest is the monoamine norepinephrine (NE). Noradrenergic dysfunction is implicated in AUD, anxiety, chronic stress, depression, and emotional and physical pain. Importantly, there are key sexual dimorphisms within the noradrenergic system that are thought to differentially impact the development and trajectory of AUD in women and men. The present review discusses past and recent work on noradrenergic influences at each stage of the AUD cycle (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) through the lens of hyperkatifeia. Evidence from these studies support the prioritization of NE-specific drug development to treat AUD and the identification of AUD subpopulations that may benefit the most from these therapies (e.g., women and people with comorbid chronic pain or anxiety/stress disorders).