A focus on alpha-1 blockade as a novel pharmacological treatment for alcohol use disorder

应激在酒精中毒的发生和持续中起着重要的作用

It has been well established that stress plays an important role in the initiation and continuation of alcohol- related behaviors. Studies indicate that individuals with alcohol use disorder (AUD) are at increased risk for the dysregulation of stress, however, currently none of the FDA-approved medications for AUD target the stress system. As such, novel pharmacological interventions targeting the noradrenergic system to regulate the stress response in individuals with AUD provide a promising therapeutic opportunity. Further, it is well-described in the literature that AUD is associated with chronic and prolonged immune inflammation. Therefore, pro/anti- inflammatory cytokines may represent an important biological mechanism that contributes to the reinforcing effect of alcohol and can be utilized as novel targets to develop AUD pharmacophore. The primary objectives of this supplement are to examine the anti-inflammatory effect of doxazosin, an alpha 1 noradrenergic receptor blocker, on serum levels of cytokines in individuals with AUD, and to assess the mediating role of inflammatory cytokines as a mechanism by which doxazosin decreases alcohol consumption. Serum samples will be collected from 184 treatment seeking individuals with AUD. Samples will be obtained at seven time points over the 12-week study: at baseline, at the maximum tolerated dose (the laboratory phase and naturalistic phase during week 5-11), and at the end of the study (week 12). Cytokine analysis using ELLA, an automated enzyme-linked immunoassay system, will be tested as a secondary outcome (Aim 1) and mediator of doxazosin on alcohol-related outcomes (Aim 2). This study will be the first to our knowledge to examine cytokines as a mediator of doxazosin’s regulation of alcohol consumption. Additionally, to further develop the “personalized” pharmacological intervention approach the exploratory aim of the supplement will evaluate sex as a biological variable and racial group as moderators of doxazosin’s effect on alcohol consumption. This Diversity Supplement will provide valuable insight further elucidating the mechanisms underlying AUD and the mechanistic actions of novel pharmacological therapies for the treatment of AUD.