A Scoping Review of Preclinical Paradigms for Clinically Tested Medications in Alcohol Use Disorder.

Abstract

Despite increasing attention to the neurobiology of alcohol use disorder (AUD), development of effective pharmacotherapies remains limited. Many medications with promising preclinical profiles fail to translate into clinical efficacy. This scoping review characterizes preclinical studies evaluating medications for AUD that have also been tested in human laboratory paradigms or clinical trials. We focus on two widely used paradigms: the two-bottle choice (2BC) task, which measures alcohol consumption and preference, and operant reinstatement models, which capture relapse-like behavior. A systematic search and data extraction identified preclinical studies using 2BC and reinstatement paradigms to evaluate medications that progressed to human testing. Study characteristics (species, strain, sex, outcomes, and sample sizes) were recorded and effect sizes (corrected Cohen's d) were summarized across outcome domains. Ninety-two unique studies met criteria: 74 employing the 2BC paradigm and 18 using operant reinstatement models, including 1731 animals. Rats were the most common species and sex bias was pronounced: 77 2BC studies using only males, five only females, and all 18 reinstatement studies used male rats exclusively. For 2BC consumption, the largest effects were observed for medications with limited studies, such as levetiracetam (d = -4.58), while more extensively tested medications showed moderate effects, including prazosin (d = -0.74) and naltrexone (d = -0.63). For 2BC preference, levetiracetam again showed a large effect in a single study (d = -4.29). In reinstatement models, rimonabant showed the largest effect (d = -3.11), while naltrexone (d = -0.70), baclofen (d = -1.05), and varenicline (d = -0.72) had moderate effects. This review highlights substantial heterogeneity in study design and underutilization of reinstatement and female animals. Medications with moderate, replicable preclinical effects, especially those tested across both 2BC and reinstatement models, may hold greater translational promise. These findings offer key opportunities for enhancing the translational alignment of preclinical AUD pharmacotherapy research.