Orexins (also named hypocretins) are recently discovered neuropeptides made exclusively in the hypothalamus. Recent studies have shown that orexin cells located specifically in lateral hypothalamus (LH) are involved in motivated behavior for drugs of abuse as well as natural rewards. Administration of orexin has been shown to stimulate food consumption, and orexin signaling in VTA has been implicated in intake of high-fat food. In self-administration studies, the orexin 1 receptor antagonist SB-334867 (SB) attenuated operant responding for high-fat pellets, sucrose pellets and ethanol, but not cocaine, demonstrating that signaling at orexin receptors is necessary for reinforcement of specific rewards. The orexin system is also implicated in associations between rewards and relevant stimuli. For example, Fos expression in LH orexin neurons varied in proportion to conditioned place preference (CPP) for food, morphine, or cocaine. This Fos expression was altered accordingly for CPP administered during protracted abstinence from morphine or cocaine, when preference for natural rewards was decreased and drug preference was increased. Additionally, orexin has been shown to be involved in reward-stimulus associations in the self-administration paradigm, where SB attenuated cue-induced reinstatement of extinguished sucrose-or cocaineseeking. Although the specific circuitry mediating the effects of orexin on food reward remains unknown, VTA seems likely to be a critical target for at least some these orexin actions. Thus, recent studies have established a role for orexin in reward-based feeding, and further investigation is warranted for determining whether function/dysfunction of the orexin system may contribute to the overeating associated with obesity.

Rationale The orexin/hypocretin system has recently been implicated in reward-seeking, especially for highly salient food and drug rewards. We reasoned that this system may be strongly engaged during periods of reward restriction, including food restriction. Objectives This study examined the involvement of the orexin (Orx) system in responding for sucrose, and in cue-induced reinstatement of extinguished sucrose-seeking, in ad libitum fed vs. food-restricted male subjects. Methods Sprague Dawley rats (n=108) were trained to self-administer sucrose, and we determined the effects of pretreatment with the OxR1 receptor antagonist SB 334867 (SB; 10–30 mg/kg) on fixed ratio (FR) or progressive ratio (PR) sucrose self-administration, as well as on cue-induced reinstatement of sucrose-seeking. Finally, expression of the immediate early gene c-fos in Orx neurons was examined after self-administration, late extinction or cue-induced reinstatement of sucrose seeking. Results SB decreased lever responding (by about 1/3) and the number of reinforcers earned during FR, and less so during PR, schedules and decreased cue-induced reinstatement to sucrose-seeking to extinction levels, predominately in food-restricted rats. Additionally, Fos expression in Orx neurons in perifornical and dorsomedial hypothalamus was increased during extinction. Conclusions These results indicate that signaling at the OxR1 receptor is involved in pronounced sucrose reinforcement, and reinstatement of sucrose-seeking elicited by sucrose-paired cues, in food-restricted subjects. These findings lead us to conclude that conditioned activation of Orx neurons increases motivation for food reward during food restriction.

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Binge eating and substance dependence are disorders characterized by a loss of control over consummatory behaviors. Given the common characteristics of these two types of disorders, it is not surprising that the comorbidity between eating disorders and substance abuse disorders is high (20–40%; Conason et al., 2006). It is unknown, however, whether loss of control in one disorder predisposes an individual to loss of control in the other. The present study, therefore, used a rodent model to test whether a history of binge eating would augment subsequent responding for cocaine. Using the limited access protocol described by Corwin et al. (1998), 45 adult male Sprague-Dawley rats were maintained on one of four dietary protocols for a period of six weeks: chow only (Chow; n=9), continuous access to an optional source of dietary fat (Ad Lib; n=12), 1-h access to an optional source of dietary fat daily (Daily; n=12), or 1-h access to an optional source of dietary fat on Monday, Wednesday, and Friday (MWF; n=12). All four groups also had unrestricted access to a nutritionally complete diet of chow and water. Fat-bingeing behaviors developed in the MWF rats, the group with the most restricted access to the optional fat. Thereafter, cocaine-seeking and –taking behaviors were assessed in all rats using a self-administration protocol modified from that described by Deroche-Gamonet et al. (2004), which focus on the motivation for and preoccupation with obtaining and consuming drug (assessed using a progressive ratio (PR) schedule of reinforcement) and persistence in responding for drug during periods of signaled drug non-availability (SNA). Rats with the MWF history tended to take more cocaine late in fixed ratio (FR) training, they persisted in their efforts to obtain cocaine in the face of signaled non-availability, worked harder for cocaine on a PR schedule of reinforcement, and exhibited more goal-directed behavior towards the cocaine-associated operandum. These results demonstrate a link between binge-type intake of fat and the development of drug-seeking and -taking behaviors, suggesting that a history of fat bingeing may predispose individuals to exhibit more robust “addiction-like” behaviors toward a substance of abuse. Thus, it appears that conditions promoting excessive behavior toward one substance (e.g., a palatable fatty food) beget excessive behavior toward another (e.g., cocaine).