Assessing the Value of the Zebrafish Conditioned Place Preference Model for Predicting Human Abuse Potential

Regulatory agencies recommend that centrally active drugs are tested for abuse potential before approval. Standard preclinical assessments are conducted in rats or non-human primates (NHPs). This study evaluated the ability of the zebrafish conditioned place preference (CPP) model to predict human abuse outcomes. Twenty-seven compounds from a variety of pharmacological classes were tested in zebrafish CPP, categorized as positive or negative, and analyzed using standard diagnostic tests of binary classification to determine the likelihood that zebrafish correctly predict robust positive signals in human subjective effects studies (+HSE) and/or Drug Enforcement Administration drug scheduling. Results were then compared with those generated for rat self-administration and CPP, as well as NHP self-administration, using this same set of compounds. The findings reveal that zebrafish concordance and sensitivity values were not significantly different from chance for both +HSE and scheduling. Although significant improvements in specificity and negative predictive values were observed for zebrafish relative to +HSE, specificity without sensitivity provides limited predictive value. Moreover, assessments in zebrafish provided no added value for predicting scheduling. By contrast, rat and NHP models generally possessed significantly improved concordance, sensitivity, and positive predictive values for both clinical measures. Although there may be predictive value with compounds from specific pharmacological classes (e.g., µ-opioid receptor agonists, psychostimulants) for zebrafish CPP, altogether these data highlight that using the current methodology, the zebrafish CPP model does not add value to the preclinical assessment of abuse potential.