Orexin Signaling Via the Orexin 1 Receptor Mediates Operant Responding for Food Reinforcement

Abstract

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.

Roles of orexins in the regulation of body weight homeostasis

“…Consistently, OX1R is shown to be involved in the reward regulation by orexin [52][53][54] . shown to be dependent on an activation of OX1R 55 .…”

Effect of orexin-B-saporin-induced lesions of the lateral hypothalamus on performance on a progressive ratio schedule

“…Evidence consistent with this proposition derives from a range of pharmacological manipulations (e.g., systemic or central administration of orexin receptor antagonists: Clegg et al, 2002;Harris et al, 2005Harris et al, , 2006Zheng et al, 2007;Borgland et al, 2009; central administration of orexin or its precursor: Choi et al., 2010), and a variety of behavioural paradigms (e.g., conditioned place preference: Harris et al, 2005Harris et al, , 2007Narita et al, 2006; consumption of palatable diet: Clegg et al, 2002;Zheng et al, 2007;Nair et al, 2008;Borgland et al, 2009;Sharf et al, 2010; performance on progressive-ratio schedules: Borgland et al, 2009;Choi et al, 2010). Several methodological factors may have contributed to the apparent discrepancy between the present findings and the results of previous experiments.…”

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

“…The role of OXs in reward-based food intake has been documented by a recent paper of Perello et al (2010), showing that the increase in the rewarding value of high-fat diet induced by ghrelin is OX-dependent; moreover, SB-334867 has been reported to inhibit high-fat food selfadministration (Nair et al, 2008). Activation of the OX 1 R is a necessary component of food-reinforced responding, motivation, or both (Sharf et al, 2010). In addition, LH OX neurons are activated by cues associated with consummatory rewards such as food (Harris et al, 2005), suggesting a potential role of the OX system in response to external environmental cues linked to cognitive aspects of feeding.…”