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Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin-1 receptor antagonist in rats

Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long (LgA) or intermittent (IntA) access self-administration schedules, both of which model the transition to uncontrolled drug seeking. Moreover, because the orexin-1 receptor antagonist SB-334867 (SB) is particularly effective at reducing drug-seeking in highly motivated individuals, we asked whether demand measured after prolonged drug experience could predict SB efficacy. Demand elasticity (α) measured immediately following acquisition of cocaine self-administration (‘baseline α’) was positively correlated with α assessed after 2w of LgA or IntA. Baseline α also predicted the magnitude of compulsive responding for cocaine, drug seeking in initial abstinence, and cued reinstatement following LgA, IntA or standard short access (ShA). When demand was measured after LgA, IntA or ShA, α predicted the same addiction endophenotypes predicted by baseline α, as well as primed reinstatement and the emergence of negative emotional mood behavior following abstinence. Post-LgA/IntA/ShA α also predicted the efficacy of SB, such that high demand rats showed greater reductions in motivation for cocaine following SB (10 and 30mg/kg) compared to low demand rats. Together, these findings indicate that α might serve as a behavioral biomarker to predict individuals most likely to progress from controlled to uncontrolled drug use, and to identify individuals most likely to benefit from orexin-based therapies for the treatment of addiction.