Sherry A. McKee

BACKGROUND: Chronic alcohol use leads to synaptic dysfunction in preclinical studies. However, whether in vivo synaptic density deficits are found in people with alcohol use disorder (AUD) remains unclear. METHODS: Thirty-two people with AUD ( n = 17 women; n = 15 men) and 29 control participants ( n = 17 women; n = 12 men)completed 1 PET brain imaging scan with the radiotracer [ ¹¹ C]UCB-J, which binds to SV2A, a marker of synaptic density. The levels of synaptic density were quantified by estimating the nondisplaceable binding potential ( BP _ND ) across 4 regions of interest: frontal cortex, striatum, hippocampus, and cerebellum. RESULTS: People with AUD were, on average (±SD), 43 ± 13 years of age, and most met the criteria for having mild or moderate AUD. The control participants were 37 ± 12 years of age. People with AUD had, on average, a 11% lower [ ¹¹ C]UCB-J BP _ND than did controls in the frontal cortex [ F _(1,62) = 13.074, P < 0.001], striatum [ F _(1,60) = 10.283, P = 0.002], and hippocampus [ F _(1,60) = 5.964, P = 0.018], trending in the same direction in the cerebellum [ F _(1,50) = 3.438, P = 0.070]. Among people with AUD, lower [ ¹¹ C]UCB-J BP _ND was significantly related to more drinks per drinking day, in the frontal cortex ( P = 0.022) and striatum ( P = 0.026). People with AUD performed worse on executive function than did controls ( P = 0.020), but this was not related to [ ¹¹ C]UCB-J BP _ND . CONCLUSION: Synaptic density deficits were evident, even in people with mild-to-moderate AUD, with larger deficits observed in those with greater drinking severity. These findings underscore the potential of synaptic restoration as a therapeutic target for AUD. FUNDING: NIH (U54AA027989, P01AA02747307, K01AA029706, and K24AA031345); UCB Pharma SA.

The alcohol cue‐exposure paradigm has a long and rich history in alcohol use disorder (AUD) research, contributing to the identification of risk factors, the recognition of craving as a core symptom, the understanding of AUD neurobiology, and the development of both pharmacological and behavioral treatments. The goal of this review was to evaluate the utility of the alcohol cue‐exposure paradigm as a screening tool for AUD medication development and to provide recommendations for refinement of the paradigm. First, we review evidence supporting the predictive validity and clinical applicability of the alcohol cue‐exposure paradigm. Second, we examine current practices in implementing the paradigm in AUD pharmacotherapy studies. Third, we highlight several areas for refinement and offer recommendations for the implementation of this paradigm. Finally, we outline key conclusions and actionable future directions. In summary, while the alcohol cue‐exposure paradigm has an established foundation in the study of AUD pharmacotherapies, its future success hinges on a concerted effort to refine and standardize protocols and validate outcome measures in large‐scale studies. Addressing these priorities could accelerate the development and regulatory approval of novel treatments for AUD.

Background: Alcohol use and alcohol use disorder (AUD) are significant contributors to morbidity and mortality, with different prevalences between males and females. Despite the established genetic contribution to AUD, sex as a biological variable and the interplay with genetic factors in the disorder remain largely unexplored. This study aimed to address the key question as to how genetic variations interact with biological sex to influence the AUD risk. Methods: We conducted genome‐wide genotype‐by‐sex (G × S) interaction analyses using multiancestry datasets from the Million Veteran Program (MVP) and UK Biobank (UKB). In total, 1,039,476 participants were analyzed, comprising 150,429 AUD cases and 889,046 controls. AUD cases were defined using ICD‐9/10 codes in the MVP and using ICD‐10 codes (field ID 41270) along with self‐reported history of alcohol addiction (field ID 20406) in the UKB. Results: In single‐ancestry analyses, we identified two loci in African ancestry samples with lead single‐nucleotide polymorphisms (SNPs) rs2183020 ( p = 1.82 × 10 ⁻⁸ ) and rs9304803 ( p = 4.66 × 10 ⁻⁸ ), and one locus in Admixed American ancestry samples with lead SNP rs9527196 ( p = 2.83 × 10 ⁻⁸ ). The cross‐ancestry meta‐analysis identified one additional locus with lead SNP rs62446539 ( p = 3.95 × 10 ⁻⁸ ). The deep learning method predicted that rs9304803 has B‐cell type‐specific enhancer activity. Rs2183020 and rs9304803 exhibited expression quantitative trait locus (eQTL) effects on multiple genes across various tissues, including the brain. Further experiments in ethanol‐exposed human neurons confirmed expression changes in several of these genes. Phenome‐wide association analyses revealed significant associations between rs2183020 and weight/body mass index, and between rs9304803 and prothrombin time (measured as international normalized ratio). Conclusions: We believe this is the first genome‐wide G × S study of AUD, providing novel insights into the genetic basis of sex differences in AUD and advancing our understanding of its biological underpinnings.