Background-The lateral hypothalamic neuropeptide, orexin (or hypocretin), is implicated in drug addiction. While a role for orexin has been shown in reward and dependence, the molecular and neural mechanisms are unclear. Here, we investigated the mechanism and neuroanatomical basis of orexin's role in morphine withdrawal.

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Background Orexin (hypocretin) signaling is implicated in drug addiction and reward, but its role in feeding and food-motivated behavior remains unclear. Methods We investigated orexin’s contribution to food-reinforced instrumental responding using an orexin 1 receptor (Ox1r) antagonist, orexin −/− (OKO) and littermate wild-type (WT) mice, and RNAi-mediated knockdown of orexin. C57BL/6J (n=76) and OKO (n=39) mice were trained to nose poke for food under a variable ratio (VR) schedule of reinforcement. Once responding stabilized, a progressive ratio (PR) schedule was initiated to evaluate motivation to obtain food reinforcement. Results Blockade of Ox1r in C57BL/6J mice impaired performance under both the VR and PR schedules of reinforcement, indicating impaired motivational processes. In contrast, OKO mice initially demonstrated a delay in acquisition, but eventually achieved levels of responding similar to those observed in WT animals. Moreover, OKO mice did not differ from WT mice under a PR schedule, indicating delayed learning processes but no motivational impairments. Considering the differences between pharmacological blockade of Ox1r and the OKO mice, animals with RNAi mediated knockdown of orexin were then generated and analyzed to eliminate possible developmental effects of missing orexin. Orexin gene knockdown in the lateral hypothalamus (LH) in C57BL/6J mice resulted in blunted performance under both the VR and PR schedules, resembling data obtained following Ox1r antagonism. Conclusions The behavior seen in OKO mice likely reflects developmental compensation often seen in mutant animals. These data suggest that activation of the Ox1r is a necessary component of food-reinforced responding and/or motivation in normal mice.

The orexins (or hypocretins) are hypothalamic neuropeptides that have been implicated in a variety of behaviors ranging from feeding to sleep and arousal. Evidence from animal models suggests a role for orexins in reward processing and drug addiction. In this review, we discuss orexin’s interaction with the mesocorticolimbic reward pathway and the effects of drugs of abuse on the orexin system. We further review models of drug dependence and addiction and describe behavioral alterations that are seen when the orexin system is manipulated both pharmacologically and genetically. Based on the findings reported in the literature thus far, we posit that orexin functioning contributes to both drug reward and drug related stress/aversive responsiveness; however, diverse anatomical substrates, and perhaps receptor specificity, contribute differentially to reward and stress components.

Orexin (or hypocretin) has been implicated in mediating drug addiction and reward. Here, we investigated orexin's contribution to morphine-induced behavioral sensitization and place preference. Orexin -/-(OKO) mice and littermate wild-type (WT) controls (n= 56) and C57BL/6J mice (n=67) were tested for chronic morphine-induced locomotor sensitization or for conditioned place preference (CPP) for a morphine-or a cocaine-paired environment. C57BL/6J mice received the orexin receptor 1 (Ox1r) antagonist, SB-334867, prior to test sessions. OKO mice did not significantly differ from WT controls in locomotor activity following acute-or chronic-morphine treatments. Similarly, mice treated with the Ox1r antagonist did not differ from vehicle controls in locomotor activity following acute-or chronic-morphine treatments. In contrast, while OKO mice did not differ from WT controls in preference for a morphine-paired environment, the Ox1r antagonist significantly attenuated place preference for a morphine-, but not a cocaine-paired, environment. These data suggest that orexin action is not required for locomotor responses to acute and chronic morphine, but Ox1r signaling can influence morphine-seeking in WT animals.

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Stimulation of VTA mAChR, but not of nAChR, is necessary for the acquisition of a food-rewarded lever-pressing task and neither is necessary for the performance of the task.

These data suggest that blockade of dendritically released DA in the SN reduces the rewarding effects of cocaine. These findings complement accumulating evidence that the rewarding effects of cocaine are not restricted to the drug's ability to elevate dopamine levels in the nucleus accumbens.