Predicting individual treatment response in alcohol use disorders: a reverse translational proof-of-concept study

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Medication development for alcohol use disorder (AUD) is hindered by a translational gap between preclinical models and clinical outcomes.
• Homogeneous animal models may fail to capture the inter-individual variability observed in human clinical cohorts, contributing to drug development failures.

Purpose of the Study:

• To investigate if a preclinical model of AUD incorporating inter-individual heterogeneity can predict the clinical efficacy of Memantine and Naltrexone.
• To assess the predictive value of accounting for individual response patterns in animal models for drug development in AUD.

Main Methods:

• NIH genetically heterogeneous-stock rats were screened for alcohol drinking, motivation, and cued reinstatement.
• The effects of Memantine and Naltrexone on alcohol (ASA) and saccharin self-administration (SSA) were tested.
• Rats were clustered into responders and non-responders based on individual drug effects, and sex differences were analyzed.

Main Results:

• Memantine reduced both alcohol and saccharin self-administration across all groups, failing to selectively target alcohol intake.
• Naltrexone selectively reduced alcohol self-administration in responder rats, with responders predominantly being male.
• Non-responders to Naltrexone showed no cued reinstatement of alcohol seeking, and sex differences in Naltrexone response were observed.

Conclusions:

• Accounting for inter-individual heterogeneity in preclinical AUD models can improve the prediction of drug efficacy, mirroring clinical observations.
• This approach identified Memantine's lack of selective efficacy and Naltrexone's efficacy in specific responders, highlighting potential sex differences.
• Utilizing inter-individual heterogeneity in preclinical studies is crucial for advancing AUD medication development and can inform clinical trial design.