Editorial: Advances in Pharmacotherapy for Alcohol Use Disorder: From Mechanisms to Clinical Interventions

Regina A Mangieri¹Sunil Sirohi²Ezequiel Marron Fernandez De Velasco³Seungwoo Kang^4*

• ¹Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, United States
• ²Laboratory of Endocrine and Neuropsychiatric Disorders, Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, United States
• ³Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, United States
• ⁴Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, United States

Pathophysiological adaptation in the striatum has been recognized as a principal brain dysfunction resulting from chronic alcohol exposure, specifically contributing to maladaptive reward-seeking behaviors (Corbit and Janak, 2016). Given the different roles of striatal subregions in shaping reward-seeking patterns and motivation, the detailed characterization of striatal adaptations to chronic alcohol consumption is important to understand the progression from voluntary to inflexible alcohol-seeking behaviors. Recent research by Duffus et al. employed mass spectrometry analysis of protein abundance in the dorsomedial, dorsolateral, and nucleus accumbens subregions of the striatum, at two different abstinence time points following chronic, voluntary alcohol drinking in male and female mice (Duffus et al., 2024). Their comprehensive proteomics data illuminated brain adaptations, such as changes in neurodegeneration-associated proteins, that differed as a function of abstinence duration, subregion, and sex. A general feature, however, was that chronic alcohol drinking appeared to primarily alter proteins important for neuronal structure and cellular health, rather than induce neuroinflammation in the striatum; proteomic profiling revealed changes in proteins and pathways associated with metabolic, cellular organization, protein translation, and molecular transport processes. These findings are in contrast to the literature linking alcohol dependence to upregulation of neuroinflammatory processes, suggesting that the role of neuroinflammation in alcohol-related behavioral changes may vary across different brain regions. On the other hand, it is not clear whether the chronic drinking model employed induces alcohol dependence, and discrepancies with prior work could also be related to differences in the degree of alcohol exposure or the abstinence time point at which proteins were measured. Nonetheless, this 40 work not only demonstrates the of subregion-specific characterization but also provides a 41 new list of proteins that establishes a foundation for future investigations of alcohol-induced changes 42 to striatal neuronal structure and cellular health their behavioral consequences. 43 Semaglutide, a long-acting analogue glucagon-like peptide-1, has emerged as an effective weight-44 loss treatment through appetite regulation in both diabetic and non-diabetic individuals. 45Accumulative evidence indicates its efficacy in weight loss-independent actions as well (Drucker, 46 2024). GLP-1 receptor agonists also have recently shown their potential as treatments for AUD in 47 rodent and nonhuman primate studies, and clinical trials to evaluate the efficacy of the agonists have 48 been initiated for AUD patients (Marty et al., 2020;Farokhnia et al., 2025;Hendershot et al., 2025). 49Aranas et al. examined, using rodent models in both male and female, the potential synergistic 50 effects of combining semaglutide with the well-known anti-smoking agents, varenicline or 51 bupropion, in the reduction of alcohol intake, while simultaneously assessing the impact of a high-fat 52 diet (HFD) (Aranas et al., 2023). Aranas et al. confirmed that semaglutide as a monotherapy 53 effectively reduced alcohol intake and preference. Notably, when semaglutide was combined with 54 either of varenicline, bupropion or HFD, it did not change the effects of semaglutide on the reduction 55 of alcohol intake, suggesting that pharmacological interventions to target GLP-1 provide sufficient 56 effects for AUD without requiring "complex combination regimens", offering the potential for 57 optimizing treatments for both AUD and obesity. Interestingly, HFD feeding in this study (Aranas et 58 al., 2023) was also found to be equally effective in reducing alcohol drinking, which is consistent 59 with several rodent studies. Considering the nutritional deficiencies following prolonged chronic 60 alcohol consumption and increased intake of palatable food in recovering patients, these data may 61 have important clinical implications in the management of AUD. While a complex relationship 62 between nutrition and AUD exists, the possibility of utilizing a non-pharmacological nutritional 63 intervention that could facilitate the pathway of recovery needs further investigation (White & Sirohi, 64 2024). 65Treatment availability for AUD continues to be limited, evident as less than 10% of patients obtain 66 any form of treatment, and even the treatment rates vary around the world (Venegas et al., 2021). 67This gap in treatment has prompted exploration of alternative medications, particularly in regions 68 where traditional practices are culturally relevant and accepted. For example, AUD and its 69 comorbidities pose significant public health challenges in Africa, where traditional medicines are also 70 suggested as a complementary and alternative option due to the limited availability of conventional 71 medications.