THE ROLE OF OREXIN-A IN FOOD MOTIVATION, REWARD-BASED FEEDING BEHAVIOR AND FOOD-INDUCED NEURONAL ACTIVATION IN RATS D. L. CHOI, 1 * J. F. DAVIS, 1 M. E. FITZGERALD AND S. C. BENOIT Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA Abstract—Consumption beyond homeostatic needs, referred to here as reward-based feeding behavior, is a central contrib- utor to the current obesity epidemic worldwide. Importantly, reward-based feeding can be driven by palatability, the taste and texture of the food, as well as cues associated with the consumption of palatable foods. The hypothalamic orexin system regulates both diet preference and anticipation of food rewards making it a likely target to modulate reward- based feeding behavior. In the current manuscript we hypoth- esized that orexin signaling mediates food-motivated behav- iors and reward-based feeding behavior. We further hypoth- esized that orexin neurons and targets of the orexin system become activated in response to cues associated with the consumption of palatable food. Data from these studies sug- gest that orexin signaling promotes progressive ratio re- sponding for palatable foods while blockade of orexin signal- ing attenuates reward-based feeding of a high fat diet. In addition, cues linked to the consumption of chocolate, or the receipt of a daily meal, activate the orexin system and its target regions differentially. Collectively, these data suggest that orexin signaling mediates reward-based feeding behav- ior and, within specific target regions, may regulate cue- induced overconsumption of palatable foods. © 2010 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: orexin, food reward, food anticipation, progres- sive ratio, non-homeostatic feeding, high fat overfeeding. Consumption beyond homeostatic needs, referred to here as “reward-based feeding behavior,” is a central contribu- tor to the current obesity epidemic worldwide (Berthoud, 2004). Over the past decade it has become increasingly clear that reward-based feeding is influenced by cognitive emotional processing within brain reward circuits (Kelley and Berridge, 2002; Saper et al., 2002; Cota et al., 2006; Zheng and Berthoud, 2007). Importantly, reward-based feeding can be driven by palatability, like the taste and texture of the food, as well as cues associated with the consumption of palatable foods. The observation that met- abolic hypothalamic circuits interface with the midbrain dopamine system to regulate feeding (DiLeone et al., 2003; Lutter and Nestler, 2009) suggests an anatomical means by which the regulation of such feeding might oc- cur. The hypothalamic orexin system has the capacity to respond to metabolic signals (Sakurai, 2007) and regulate feeding behavior through its effects on mesolimbic reward circuitry (Zheng et al., 2007) making it a likely candidate to modulate reward-based feeding behavior. In particular, orexin neurons in the lateral hypothala- mus (LH) are activated in response to hypoglycemia (Cai et al., 1999; Moriguchi et al., 1999), caloric restriction (Sakurai et al., 1998) and systemic leptin administration (Lopez et al., 2000) suggesting that this system is respon- sive to internal homeostatic signals in place to maintain energy homeostasis. Interestingly, LH orexin neurons are also activated in anticipation of palatable food rewards (Harris et al., 2005) illustrating the ability of the orexin system to respond to external environmental cues linked to the cognitive aspects of feeding. Environmental cues are potent inducers of feeding in both humans and rodents (Weingarten, 1983; Cornell et al., 1989; Rogers and Hill, 1989; Petrovich et al., 2005, 2007) even when energy levels are satisfied. Thus, anticipation of feeding repre- sents a critical point of regulation in regards to reward- based feeding behavior. Taken together, these data sug- gest that orexin neurons become activated by circulating factors and cues which induce feeding. In addition to its ability to regulate anticipation of feed- ing, the hypothalamic orexin system also regulates feeding and food reward behaviors. Central administration of orexin-A induces feeding behavior and preferential con- sumption of high fat diet (Sakurai et al., 1998; Clegg et al., 2002). Receptors for orexin peptides are present in both hypothalamic and mesolimbic regions which regulate food hedonics (Trivedi et al., 1998; Hervieu et al., 2001; Marcus et al., 2001) suggesting that orexins may regulate food intake and diet selection by signaling within mesolimbic regions. In support of this notion, direct application of orexin into the ventral tegmental area (VTA) induces do- pamine release in the nucleus accumbens (NAcc) (Narita et al., 2006). Moreover, blockade of orexin signaling within the VTA attenuates opioid-driven feeding behavior (Zheng et al., 2007) and psychostimulant-induced neuroadapta- tions within VTA neurons (Borgland et al., 2006). Collec- tively, these data suggest that the orexin signaling pro- motes feeding behavior through modulation of brain re- ward circuits. 1 Both authors contributed equally to the preparation of this manu- script. *Corresponding author. Tel: +1-513-558-6468. E-mail address: choidl@mail.uc.edu (D. L. Choi). Abbreviations: ANOVA, analysis of variance; HFD, high fat diet; IR, immunoreactivity; LH, lateral hypothalamus; mPFC, medial prefrontal cortex; NAcc, nucleus accumbens; OX1R, orexin-1 receptor; PFA–LH, perifornical area and lateral hypothalamus; PR, progressive ratio; PVT, paraventricular thalamus; RT, room temperature; VTA, ventral tegmental area. Neuroscience 167 (2010) 11–20 0306-4522/10 $ - see front matter © 2010 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2010.02.002 11