WSU study first
WSU study first to determine best method of preclinical testing for alcohol use disorder medications
A newly published study conducted by a Wayne State University School of Medicine researcher is the first to show which animal testing method might be more useful in predicting how well an alcohol use disorder medication will work in humans.
Published in the journal Translational Psychiatry, “Translating medication effects for alcohol use disorder across preclinical, human laboratory, and clinical trial outcomes using meta-analysis” provides critical support for the translational validity of preclinical animal models in medication development for alcohol use disorder in humans, said lead author Steven Nieto, Ph.D., assistant professor of Psychiatry and Behavioral Neurosciences at Wayne State University.
Before new medications for alcohol use disorder, or AUD, are tested in people, they usually go through a series of animal studies. The tests are meant to predict whether a treatment might be effective in humans, but until now, scientists haven’t had strong data to show which tests are the best predictors of success in humans. The choice of how to test AUD medications in animals -- called “preclinical models” -- has mostly been based on tradition or expert opinion, not hard data, Dr. Nieto said.
Dr. Nieto’s study set out to answer this question by examining two of the most commonly used tests: the “2-bottle choice” test and the “operant reinstatement” model. In the typical 2-bottle test, animals are given access to both water and alcohol, and researchers measure how often they choose alcohol over water. The operant reinstatement model is designed to mimic alcohol craving and relapse. Animals are trained to press a lever to receive alcohol. After the alcohol is taken away, scientists test whether certain triggers—like stress or alcohol-related cues—cause the animals to start pressing the lever again.
The researchers compared how medications performed in these tests to how they performed in human clinical trials. They found that when a medication reduced how often animals chose alcohol in the 2-bottle test, that medication was more likely to help people avoid relapse in clinical trials.
The operant reinstatement model also showed promise. Medications that made animals less likely to seek alcohol—meaning they pressed the lever fewer times after being triggered—were somewhat linked to better outcomes in people. However, the evidence wasn’t as strong, likely because fewer studies had data available for comparison.
The findings are significant because they provide some of the first data-driven insights into which preclinical models may actually help predict a medication’s success in treating AUD. By focusing on models that reflect alcohol preference and craving-like behavior, researchers may be able to better target promising treatments and avoid wasting time and resources on methods that don’t translate to human results.
“This study provides empirical support for the association between medication effects across species and experimental models, a critical, yet untested, premise of preclinical studies in medications development,” Dr. Nieto said. “In addition, this is the first study to provide quantitative data to help guide the decision of which preclinical endpoint to use as an early efficacy signal in AUD medication development. Future work can apply the methods used in the current study to test the utility of other preclinical models in predicting medication effects in the human laboratory and in randomized clinical trials.”
The study and authors were supported by funds from the National Institute on Alcohol Abuse and Alcoholism (K24AA025704 and R21AA029771; F32AA029288 and R01AA029701-01S1; and F31AA029295).
