We provide the first evidence that lateral hypothalamic orexin system function extends beyond general reward seeking to play a critical role in expression of a multiphenotype addiction-like state. Thus, the orexin system is a potential novel target for pharmacotherapies designed to treat cocaine addiction. In addition, these data point to the IntA model as a preferred approach to modeling addiction-like behavior in rats.

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Background: The orexin system is important for reward-driven motivation but has not been implicated in the expression of a multi-phenotype addicted state.Methods: Rats were assessed for economic demand for cocaine prior to and following 14d of short-(ShA), long-(LgA) or intermittent-access (IntA) to cocaine. Rats were also assessed for a number of other DSM-V-relevant addiction criteria following differential access conditions. Orexin system function was assessed by i) quantification of numbers and activity of orexin cells, ii) pharmacological blockade of the orexin-1 receptor, and iii) subregion-specific knockdown of orexin cell populations.Results: IntA produced a cluster of addiction-like behaviors that closely recapitulate key diagnostic criteria for addiction to a greater extent than LgA or ShA. IntA was associated with plasticity in orexin cell function, including increased number and activity of orexin-expressing neurons within the lateral hypothalamic (LH) subregion. This plasticity persisted during protracted withdrawal from cocaine for at least 6 months and was associated with enhanced incubation of craving. Selective knockdown of LH orexin neurons reversed the addicted state, and orexin-1 receptor signaling played a larger role in drug seeking after IntA.Conclusions: These data provide the first evidence that LH orexin system function extends beyond general reward seeking to play a critical role in the expression of a multi-phenotype addicted-like state. Thus, the orexin/hypocretin system is a potential novel target for pharmacotherapies designed to treat cocaine addiction. In addition, these data point to the IntA model as a preferred approach to modeling addictionlike behavior 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‐ or intermittent access self‐administration schedules, both of which model the transition to uncontrolled drug‐seeking. Because the orexin‐1 receptor antagonist SB‐334867 (SB) is particularly effective at reducing drug‐seeking in highly motivated individuals, we also 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 long‐ or intermittent access. Baseline α also predicted the magnitude of compulsive responding for cocaine, drug‐seeking in initial abstinence and cued reinstatement following long‐, intermittent‐ or standard short access. When demand was measured after these differential access conditions, 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. α also predicted the efficacy of SB, such that high demand rats showed greater reductions in motivation for cocaine following SB 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.