Increased number and activity of a lateral subpopulation of hypothalamic orexin/hypocretin neurons underlies the expression of an addicted state in rats

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 accompanied by an increase in the number and activity of orexin-expressing neurons within the lateral hypothalamic (LH) subregion. This increase in orexin cell number/activity persisted during protracted withdrawal from cocaine for at least 6 months and was accompanied by enhanced incubation of craving in the same rats. 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: We 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 addiction-like behavior in rats.